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Bioinformatics in MicroRNA Research 1st Edition Coll.
Digital Instant Download
Author(s): coll.
ISBN(s): 9781493970445, 1493970445
Edition: 1st
File Details: PDF, 5.13 MB
Year: 2017
Language: english
Methods in
Molecular Biology 1617
Jingshan Huang · Glen M. Borchert

Dejing Dou · Jun (Luke) Huan
Wenjun Lan · Ming Tan · Bin Wu
Editors
Bioinformatics
in MicroRNA
Research
Methods in Molecular Biology
Series Editor:
John M. Walker
School of Life and Medical Sciences
University of Hertfordshire
Hatfield, Hertfordshire, AL10 9AB, UK
For further volumes:

http://www.springer.com/series/7651
Bioinformatics in MicroRNA
Research
Editors
Jingshan Huang
School of Computing, University of South Alabama, Mobile, AL, USA
Glen M. Borchert
Department of Pharmacology, University of South Alabama, Mobile, AL, USA;
Department of Biology, University of South Alabama, Mobile, AL, USA
Dejing Dou
Department of Computer and Information Science, University of Oregon, Eugene, OR, USA
Jun (Luke) Huan

Department of Electrical Engineering and Computer Science, University of Kansas, Lawrence, KS, USA
Wenjun Lan
School of Bio-Engineering, Qilu University of Technology, Jinan, Shandong, China
Ming Tan
Mitchel Cancer Institute, University of South Alabama, Mobile, AL, USA
Bin Wu
Department of Endocrinology, First Affiliated Hospital, Kunming Medical University, Kunming, Yunnan, China
Editors
Jingshan Huang Glen M. Borchert
School of Computing Department of Pharmacology
University of South Alabama University of South Alabama
Mobile, AL, USA Mobile, AL, USA
Department of Biology
Dejing Dou
University of South Alabama
Department of Computer
Mobile, AL, USA
and Information Science
University of Oregon
Jun (Luke) Huan
Eugene, OR, USA
Department of Electrical Engineering
and Computer Science
Wenjun Lan
University of Kansas
School of Bioengineering
Lawrence, KS, USA
Qilu University of Technology
Jinan, Shandong, China
Ming Tan
Mitchel Cancer Institute
Bin Wu
University of South Alabama
Department of Endocrinology
Mobile, AL, USA
First Affiliated Hospital
Kunming Medical University
Kunming, Yunnan, China
ISSN 1064-3745 ISSN 1940-6029 (electronic)

Methods in Molecular Biology
ISBN 978-1-4939-7044-5 ISBN 978-1-4939-7046-9 (eBook)
DOI 10.1007/978-1-4939-7046-9
Library of Congress Control Number: 2017937362
© Springer Science+Business Media LLC 2017

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Preface
As a special class of noncoding RNAs, microRNAs (miRNAs or miRs for short) have been
reported to perform important roles in various biological and pathological processes by
regulating respective target genes. To completely understand and fully delineate miR func-
tions, besides performing biological experiments and querying PubMed and TarBase for
biologically validated miR targets, biologists can also query various miR target prediction
databases/websites for computationally predicted targets. More often than not, biologists
need to extract additional information for each and every miR target, either validated or
putative, with regard to its related information such as protein functions and affiliated sig-
naling pathways. In short, biologists are facing significant barriers in fully delineating miR
functions and the following effective bio-curation. Therefore, there is an urgent need for a
comprehensive book focusing on miR target genes, miR regulation mechanisms, miR func-
tions performed in various human diseases, and miR databases/knowledge bases.
This book is intended to give an in-depth introduction to and discussion of miRs and
their targets, miR functions, and computational techniques applied in miR research. The
primary audience includes, but is not limited to, computational biologists, computer scien-
tists, bioinformaticians, bench biologists, and clinical investigators. No prior knowledge of
computer science, databases, semantic technologies, or molecular biology is assumed. But we
do assume that readers have some biology background knowledge at the high-school level.
A brief overview of the book structure is as follows. Chapter 1 introduces the concepts of
miRs and long noncoding RNAs (lncRNAs) as well as some recent advances in miR/lncRNA
biology. Chapters 2, 3, and 4 discuss protein participants in miR regulation; viral microRNAs,
host miRs regulating viruses, and bacterial miR-like RNAs; and biomarkers, diagnostics, and
therapeutics aspects of miRs, respectively. Chapter 5 introduces basic concepts of relational
databases and biomedical big data. Chapter 6 provides an overview of semantic technologies
and bio-ontologies. Chapter 7 discusses genome-wide analysis of miR-regulated transcripts.
Chapters 8 and 9 describe in detail computational prediction of miR target genes, regulatory
interactions between miRs and their targets, as well as an introduction of various miR target
prediction databases and relevant Web resources. Chapter 10 discusses some limitations of
existing approaches that aim to improve miR target prediction accuracy. Chapters 11 and 12
introduce genomic regulation of miR expression in disease development and next generation
sequencing for miR expression profile. Chapters 13 through 16 discuss advanced topics in
computational/bioinformatics approaches in miR research, including the handling of high-
dimension data, identification and removal of noisy data, logical reasoning, and machine
learning techniques. Finally, Chapters 17–19 introduce some advances of miR research in
three human diseases: diabetes, obesity, and thyroid carcinoma.
Mobile, AL, USA Jingshan Huang

Mobile, AL, USA Glen M. Borchert
Eugene, OR, USA Dejing Dou
Lawrence, KS, USA Jun (Luke) Huan
Jinan, Shandong, China Wenjun Lan
Mobile, AL, USA Ming Tan
Kunming, Yunnan, China Bin Wu
v
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix
1 MicroRNAs, Long Noncoding RNAs, and Their Functions

in Human Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Min Xue, Ying Zhuo, and Bin Shan
2 MicroRNA Expression: Protein Participants in MicroRNA Regulation . . . . . . . . . . 27
Valeria M. King and Glen M. Borchert
3 Viral MicroRNAs, Host MicroRNAs Regulating Viruses,
and Bacterial MicroRNA-Like RNAs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Sara-Elizabeth Cardin and Glen M. Borchert
4 MicroRNAs: Biomarkers, Diagnostics, and Therapeutics . . . . . . . . . . . . . . . . . . . . 57
Weili Huang
5 Relational Databases and Biomedical Big Data . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
N.H. Nisansa D. de Silva
6 Semantic Technologies and Bio-Ontologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
Fernando Gutierrez
7 Genome-Wide Analysis of MicroRNA-Regulated Transcripts . . . . . . . . . . . . . . . . . 93
David Chevalier and Glen M. Borchert
8 Computational Prediction of MicroRNA Target Genes,
Target Prediction Databases, and Web Resources . . . . . . . . . . . . . . . . . . . . . . . . . . 109
Justin T. Roberts and Glen M. Borchert
9 Exploring MicroRNA::Target Regulatory Interactions
by Computing Technologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
Yue Hu, Wenjun Lan, and Daniel Miller
10 The Limitations of Existing Approaches in Improving MicroRNA
Target Prediction Accuracy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Rasiah Loganantharaj and Thomas A. Randall
11 Genomic Regulation of MicroRNA Expression
in Disease Development . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
Feng Liu
12 Next-Generation Sequencing for MicroRNA Expression Profile . . . . . . . . . . . . . . . 169
13 Handling High-Dimension (High-Feature) MicroRNA Data . . . . . . . . . . . . . . . . . 179
14 Effective Removal of Noisy Data Via Batch Effect Processing . . . . . . . . . . . . . . . . . 187
Ryan G. Benton
15 Logical Reasoning (Inferencing) on MicroRNA Data . . . . . . . . . . . . . . . . . . . . . . . 197
Jingsong Wang
vii
viii Contents
16 Machine Learning Techniques in Exploring MicroRNA Gene Discovery,

Targets, and Functions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 211
Sumi Singh, Ryan G. Benton, Anurag Singh, and Anshuman Singh
17 Involvement of MicroRNAs in Diabetes and Its Complications . . . . . . . . . . . . . . . 225
Bin Wu and Daniel Miller
18 MicroRNA Regulatory Networks as Biomarkers in Obesity:
The Emerging Role . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241
Lihua Zhang, Daniel Miller, Qiuping Yang, and Bin Wu
19 Expression of MicroRNAs in Thyroid Carcinoma . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Gaohong Zhu, Lijun Xie, and Daniel Miller
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281
Contributors
Ryan G. Benton • Department of Computer Science, University of South Alabama

School of Computing, Mobile, AL, USA
Glen M. Borchert • Department of Pharmacology, University of South Alabama,
Mobile, AL, USA; Department of Biology, University of South Alabama, Mobile, AL,
USA
Sara-Elizabeth Cardin • Department of Biology, University of South Alabama,
Mobile, AL, USA
David Chevalier • Department of Biology, East Georgia State College, Swainsboro,
GA, USA
N.H. Nisansa D. de Silva • Department of Computer and Information Science,
University of Oregon, Eugene, OR, USA
Fernando Gutierrez • Department of Computer and Information Science,
University of Oregon, Eugene, OR, USA
Yue Hu • College of Bioengineering, Qilu University of Technology, Jinan, Shandong,
People’s Republic of China
Weili Huang • Miracle Query, Incorporated, Eugene, OR, USA
Valeria M. King • Department of Biology, University of South Alabama, Mobile, AL, USA
Wenjun Lan • School of Bioengineering, Qilu University of Technology, Jinan,
Shandong, People’s Republic of China
Feng Liu • National Research Center for Translational Medicine (Shanghai), Rui-Jin
Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Rasiah Loganantharaj • Bioinformatics Research Lab, The Center for Advanced
Computer Studies, University of Louisiana, Lafayette, LA, USA
Daniel Miller • School of Computing, University of South Alabama, Mobile, AL, USA
Thomas A. Randall • Integrative Bioinformatics, National Institute of Environmental
Health Sciences, National Institutes of Health, Research Triangle Park, Durham,
NC, USA
Justin T. Roberts • Department of Biology, University of South Alabama,
Mobile, AL, USA
Bin Shan • Elson S. Floyd College of Medicine, Washington State University, Spokane,
WA, USA
Anshuman Singh • School of Computer Science and Mathematics, University of
Central Missouri, Warrensburg, MO, USA
Anurag Singh • Center for Advanced Computer Studies, University of Louisiana,
Lafayette, LA, USA
Sumi Singh • School of Computer Science and Mathematics, University of Central
Missouri, Warrensburg, MO, USA
Jingsong Wang • Oracle Corporation, Redwood Shores, CA, USA
Bin Wu • Department of Endocrinology, First Affiliated Hospital, Kunming Medical
University, Kunming, Yunnan, China
ix
x Contributors
Lijun Xie • Department of Nuclear Medicine, First Affiliated Hospital of Kunming

Medical University, Kunming, Yunnan, China
Min Xue • Xuzhou College of Medicine, Xuzhou, Jiangsu, China
Qiuping Yang • Department of Geriatrics, First Affiliated Hospital of Kunming
Lihua Zhang • Department of Geriatrics, First Affiliated Hospital of Kunming
Gaohong Zhu • Department of Nuclear Medicine, First Affiliated Hospital
of Kunming Medical University, Kunming, Yunnan, China
Ying Zhuo • Kadlec Regional Medical Center, Richland, WA, USA
Chapter 1
MicroRNAs, Long Noncoding RNAs, and Their Functions

in Human Disease
Min Xue, Ying Zhuo, and Bin Shan
Abstract
Majority of the human genome is transcribed into RNAs with absent or limited protein-coding potential.
microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) are two major families of the non-protein-
coding transcripts. miRNAs and lncRNAs can regulate fundamental cellular processes via diverse mecha-
nisms. The expression and function of miRNAs and lncRNAs are tightly regulated in development and
physiological homeostasis. Dysregulation of miRNAs and lncRNAs is critical to pathogenesis of human
disease. Moreover, recent evidence indicates a cross talk between miRNAs and lncRNAs. Herein we
review recent advances in the biology of miRNAs and lncRNAs with respect to the above aspects. We
focus on their roles in cancer, respiratory disease, and neurodegenerative disease. The complexity, flexibil-
ity, and versatility of the structures and functions of miRNAs and lncRNAs demand integration of experi-
mental and bioinformatics tools to acquire sufficient knowledge for applications of these noncoding
RNAs in clinical care.
Key words MicroRNA, Long noncoding RNA
1 Introduction
Majority of the human genome is transcribed although only ~2%

of the human genome encodes proteins [1]. The transcribed
RNAs with absent or limited protein-coding potential are named
noncoding RNAs and operationally divided into small RNAs and
long noncoding RNAs (lncRNA) with a boundary set at 200
nucleotides in length. The small RNA family includes microR-
NAs (miRNA), small nuclear RNAs, and piwi-interacting RNAs.
miRNAs and lncRNAs are critical regulators of development,
physiology, and disease. Herein we review recent advances in the
biology of miRNAs and lncRNAs and their functions in human
disease.
Jingshan Huang et al. (eds.), Bioinformatics in MicroRNA Research, Methods in Molecular Biology, vol. 1617,
DOI 10.1007/978-1-4939-7046-9_1, © Springer Science+Business Media LLC 2017
1
2 Min Xue et al.
2 Functions of miRNAs and Human Disease
2.1 Biogenesis miRNAs are ~22-nucleotide long single stranded RNAs that regu-
of miRNAs late gene expression via diverse mechanisms [2]. Since discovery of
the first miRNA lin-4 in Caenorhabditis elegans in 1993, 35,828
mature miRNAs have been catalogued in 223 species in the latest
release of miRBase (www.mirbase.org) [3, 4]. Biogenesis of miR-
NAs starts with transcription from a miRNA-hosting gene, which
yields a long primary transcript named primary miRNA (pri-
miRNA) [5]. Then the pri-miRNA is cleaved by the ribonulease
III-type protein Drosha in the nucleus to produce a ~70-nucleotide
long hairpin structure named precursor miRNA (pre-miRNA) [6].
The pre-miRNA is exported to the cytoplasm by exportin-5 and
subsequently cleaved by another ribonulease III-type protein Dicer
to generate a miRNA:miRNA* duplex of ~22 nucleodtides [7].
The miRNA:miRNA* duplex binds to an argonaute (AGO) pro-
tein to form an effector RNA-induced silencing complex (RISC)
complex. A mature miRNA is produced when miRNA* is peeled
off from the duplex. It is noteworthy that a miRNA* is not simply
a nonfunctional byproduct of miRNA biogenesis but rather a func-
tional miRNA on many occasions [8].
Besides their canonical destination in the cytoplasm miRNAs
exist and function in the nucleus and secretary microvesicles called
exosomes [9, 10]. Exosomes are small extracellular membrane ves-
icles with sizes of 30–100 nm in diameter and secreted by various
types of cells in the body [11–14]. miRNAs packaged in exosomes
can be taken up by neighboring cells or distant recipient cells via
transportation in body fluids and function in their recipient cells,
which serve as an important tool for proximal and distant intercel-
lular communications [15–18].
Biogenesis of miRNAs can be regulated at every step of their
production by physiological and pathological signals. For instance
the miRNA-200 family is transcriptionally suppressed by ZEB1
during epithelial–mesenchymal transition (EMT) [19]. In another
example type I collagen posttranscriptionally upregulates the
expression of miR-21 by promoting maturation of pre-miR-21 to
miR-21 without alteration in the amount of pri-miRNA-21 and
pre-miR-21 [20].
2.2 Functions The classic mode of a miRNA’s action is to inhibit gene expression
of miRNA via binding to its complementary sequences (6–8 nucleotides)
within the 3′ untranslated region (3′ UTR) of its target mRNAs.
This partial complementarity causes inhibition of expression of a
miRNA’s target via degradation or repression of translation of the
bound mRNAs [21]. Because of the need of only a 6–8 nucleotide
complementarity a miRNA can potentially targets hundreds of
mRNAs and most mammalian mRNAs are conserved targets of
MicroRNAs, Long Noncoding RNAs, and Their Functions in Human Disease 3
miRNAs [22]. Bioinformatic tools such as TargetScan have been

widely used to guide prediction and validation of a miRNA’s target
mRNAs [23].
The cytoplasmic miRNAs inhibit their target genes expression
via degradation of mRNAs or inhibition of translation at initiation
and post-initiation steps [21, 24–31]. miRNA-mediated decrease
of their target mRNA levels is proposed as a major mechanism of
miRNA-mediated repression of a target gene expression [32]. This
action can be achieved through miRNA-induced rapid deadenyl-
ation of target mRNA as exemplified by the actions of miR-125b,
a miRNA that is linked to chemoresistance in breast cancer [31,
33, 34]. miRNA-mediated suppression of translation initiation is
exemplified in let-7-mediated repression of its target mRNAs as
let-7-bound AGO2 represses the translation initiation by binding
to the m7G cap of the mRNA targets and thereby prevents the
recruitment of eIF4E, an essential translation initiation factor [35].
The post-initiation inhibition of translation by miRNAs is accom-
plished through rapid degradation of the peptide product encoded
by the targeted mRNA, which is mediated by high rate of ribo-
some drop-off during translation elongation [36].
In addition to their canonical actions in the cytoplasm miR-
NAs are expressed in abundance in the nucleus and regulate vari-
ous nuclear events such as transcription and RNA splicing via
diverse mechanisms. For instance miR-320 recruits AGO1 and
EZH2 to the POLR3D locus through complete complementary
binding, which results in heterochromatinization and silencing of
the POLR3D promoter [37]. miRNA-mediated silencing of the
gene promoters harboring their target sites controls a variety of
fundamental cellular processes, such as cellular senescence and
neuroregeneration [38–40]. On the other hand, a few nuclear
miRNAs have been reported to activate gene expression via epi-
genetic mechanisms. For instance miR-373 activates the expres-
sion of CDH1 and CSDC2 via AGO-miRNA complexes-mediated
recruitment of positive epigenetic regulators to the target promot-
ers [41]. Lastly nuclear miRNAs can regulate splicing of the com-
plement pre-mRNA. In miR-122-mediated repression of splicing
of the hepatitis C viral RNA a ternary complex formed between the
target transcript, miRNA, and RISC masks splicing recognition
motifs and thereby prevents binding of the splicing factors [42].
2.3 miRNAs miRNAs govern fundamental biological processes, such as cell pro-
and Human Disease liferation, death, differentiation, and development [43]. As a
feedback tool with profound effects on gene expression miRNAs
are the main tool to fine-tune gene expression and biological
homeostasis. Dysregulation of miRNAs contributes to pathogen-
esis of a wide variety of human disease. In this section we review
actions of miRNAs in cancer, respiratory disease, and neurodegen-
erative disease.
4 Min Xue et al.
2.3.1 miRNAs in Cancer The first documented association between miRNAs and cancer is
frequent deletion and downregulation of miR-15 and miR-16 at
13q14 in chronic lymphocytic leukemia [44]. Since then, thou-
sands of miRNAs have been reported to act as either oncogenes or
tumor suppressors depending on a miRNA’s targets in a particular
biological context. miRNAs have been linked to each hallmark of
cancer that is established by Hanahan and Weinberg [45].
Representative miRNAs associated with each hallmark of cancer
are listed in Table 1 [46–62].
Genetic alterations are a common cause of dysregulation of
miRNAs in cancer. More than 50% of miRNA genes are located in
cancer associated genomic regions or in fragile sites [63]. One
prime example is amplification of the oncogenic miR-17~92 clus-
ter and its consequent overexpression in small cell lung cancer
[47]. Deletion and loss of expression of miRNAs in cancer are
exemplified in frequent deletion of the miR-15a and miR-16a
Table 1
Association between miRNA and hallmarks of cancer
Hallmarks of cancer Representative miRNAs

Sustaining proliferative signaling miR-17~92-mediated suppression of PTEN in lung cancer and
B-cell lymphoma [46, 47]; Loss of let-7-mediated suppression of
Ras by in lung cancer [48, 49]
Evading growth suppressors Interference of cell cycle arrest by miR-675-mediated suppression
of pRB in colorectal cancer [50]
Avoiding immune destruction Enhancement of resistance to cytotoxic T-lymphocytes by
miR-222 mediated suppression of ICAM-1 [51]
Enabling replicative immortality Loss of miR-34a-mediated senescence in colon cancer [52]
Tumor promoting inflammation miR-155-mediated inflammation in the tumor microenvironment
[53, 54]
Activating invasion and metastasis miR-10b-mediated migration, invasion, and metastasis in breast
cancer [62]; Loss of miR-200-mediated suppression of EMT
[55, 56]
Inducing angiogenesis Enhanced angiogenesis by miR-296-mediated suppression of
HGS in tumor associated endothelial cells in gliomas [57]
Genome instability and mutation Impairment of DNA repair by miR-21-mediated suppression of
H2AX, a histone variant essential to repair [58, 59]
Resisting cell death Inhibition of caspase activation by miR-21-mediated suppression
of PDCD4 in glioblastoma [60]
Deregulating cellular energetics Loss of miR-99a/100-mediated suppression of mTOR in
childhood adrenocortical tumors [61]
A summary of representative miRNAs associated with the hallmarks of cancer. PTEN phosphatase and tensin homolog,
pRB retinoblastoma protein, EMT epithelial–mesenchymal transition, HGS hepatocyte growth factor-regulated tyrosine
kinase substrate, PDCD4 programmed cell death protein 4, mTOR mechanistic target of rapamycin
hosting locus in chronic lymphocytic leukemia [44]. Single nucle-

otide polymorphism (SNP) is another common cause of dysregula-
tion of miRNAs in cancer. In a common G/C polymorphism
(rs2910164) within the pre-miR-146a coding region the C allele
results in a decrease of mature miR-146a and less efficient inhibi-
tion of the miR-146a targets, which increases risk of papillary thy-
roid carcinoma [64]. Variation within the miRNA target site of a
miRNA-targeted 3′UTR is another important source of genetic
predisposition in cancer risk. In the oncogenic HMGA2 locus the
open reading frame and the 3′UTR harboring the let-7 target sites
are separated by chromosomal rearrangements in cancer, which
leads to escape of HMGA2 from let-7-mediated repression [65, 66].
SNP in a miRNA target site can result in loss of miRNA-mediated
repression in cancer. In the let-7 target site within the 3′UTR of
the KRAS oncogene SNP causes elevated KRAS expression and
increased risk of non-small cell lung cancer [67].
Transcriptional dysregulation of miRNA expression is another
critical mechanism in tumorigenesis. The oncogenic miRNAs are
often transcriptionally activated in cancer [68]. For instance the
oncogenic miR-17~92 cluster is transcriptionally activated by the
MYC oncogene via a MYC binding site in the promoter of the
miR-17~92 cluster [69]. In contrast the tumor suppressive miR-
NAs are often transcriptionally repressed in cancer [70]. The pro-
moter of the miR-200 cluster that encodes miR-200a, miR-200b,
and miR-429 is transcriptionally repressed by ZEB1 and SIP1 dur-
ing EMT, a process through which cancer cells acquire invasive
and metastatic competency [19, 55]. More importantly the miR-
200 cluster members repress the expression of ZEB1 and SIP1 via
the miR-200 target sites in their 3′ UTR and this reciprocal repres-
sion between the miR-200 cluster and ZEB1/SIP1 establishes a
double-negative feedback loop in regulation of EMT [19, 55].
miRNA expression can also be regulated by the signals from the
tumor microenvironment, such as extracellular matrix, and in turn
mediates cancer cell’s responses to the tumor microenvironment
[20, 56, 71, 72].
Because of the critical roles of miRNAs in cancer biology miR-
NAs have emerged as a family of promising targets in diagnosis and
treatment of cancer. Because miRNAs are more stable than mRNAs
and released by a solid tumor into the body fluids via exosomes
miRNAs have emerged as promising biomarkers in tissue biopsies,
blood, urine, etc. [73–75]. For instance a host of circulating miR-
NAs including miR-141, miR-21, and miR-92a have been tested
as diagnostic biomarkers of colorectal cancer in whole plasma or
serum [76–81]. miRNAs have also been developed as molecular
signatures of subtypes of breast cancer and thus guide the treat-
ment that is tailored for each molecular subtype. The miRNA sig-
natures of ER+ and HER+ can guide anti-ER and anti-HER2
therapies, respectively [82–84]. miRNAs can potentially predict
6 Min Xue et al.
responses to chemotherapy and thus guide the choice of treat-

ments as illustrated in the miRNA signatures that can predict
response to tamoxifen and anti-HER2 monoclonal antibody
Herceptin in breast cancer [85–87].
Current development of miRNA-based therapies mainly
employs antagonist and oligonucleotide mimics of a miRNA of
interest. miRNA mimics are used to restore tumor suppressive
miRNAs that are deficient in cancer. On the contrary antagomiRs
are single-stranded oligonucleotides that complement and inhibit
the oncogenic miRNAs in cancer. To increase efficiency of a
miRNA antagonist, miRNA sponge technology has been developed
to synthesize a single stranded RNA containing multiple binding
sites of a targeted miRNA to efficiently neutralize a miRNA [88].
miRNA sponges have been validated in xenograft mouse model of
human breast cancer cell lines in that inhibition of miRNA-9 and
miR-150 using a synthetic RNA containing several miR-9 or miR-
150 binding sites reduced lung metastases [89, 90]. The miRNA
targeting therapies have entered clinical trials as exemplified by a
miR-34a mimics in phase I study (http://clinicaltrials.gov/ct2/
show/NCT01829971). Preliminary results from the translational
studies of miRNA-based therapies against cancer suggest that
miRNA mimics or antagomiRs can be easily administered through
local or parenteral injection routes with sufficient uptake of the
agents to achieve sustained and desired effects in the targeted tis-
sues and organs.
2.3.2 miRNAs miRNAs have emerged as critical regulators in the control of nervous
in Neurodegenerative system-specific gene expression during development, aging, and dis-
Disease ease. We review the role of miRNAs in two devastating neurodegen-
erative diseases, Parkinson’s disease and Alzheimer’s disease.
Parkinson’s disease is a chronic and progressive movement dis-
order that is caused by a gradual loss of midbrain dopaminergic
neurons [91]. Investigation of miRNAs has shed light on patho-
genesis of Parkinson’s disease. miR-133b is specifically expressed in
the midbrain dopaminergic neurons and regulates maturation and
function of the midbrain dopaminergic neurons as a node of a neg-
ative feedback circuit by targeting the paired-like homeodomain
transcription factor Pitx3 [92]. Importantly, miR-133b is deficient
in the midbrain tissues from patients with Parkinson’s disease [92].
Gain-of-function mutations in leucine-rich repeat kinase-2
(LRRK2) cause familial and sporadic Parkinson’s disease. The
pathogenic LRRK2 associate with RISC to interfere the miRNA
pathway and such interference leads to overproduction of E2F1/DP,
a target of let-7 and miR-184* [93]. Moreover, antagomiR-
mediated blockage of let-7 or miR-184* can recapitulate the toxic
effects of the pathogenic LRRK2 and conversely forced expression
of let-7 or miR-184* can attenuate the toxic effects of the patho-
genic LRRK2 [93].
Alzheimer’s disease is the most common cause of dementia in

the aging population. The pathologic hallmarks of the disease are
plaques composed of amyloid β and tangles composed of hyper-
phosphorylated tau [94]. Several miRNA profiling studies have
identified dozens of miRNAs that are significantly differentially
expressed between cortex from patients with Alzheimer’s disease
and the matching controls [95–97]. The differentially expressed
miRNAs appear to be more robust and reproducible than the dif-
ferentially expressed mRNAs [98]. Moreover, a joint profiling of
miRNA and mRNA expression in brain cortex from Alzheimer’s
disease and age-matched control subjects reveals strong inverse
correlations between the amount of miRNAs and their corre-
sponding predicted mRNA targets, which suggests active
microRNA functions in Alzheimer’s disease [99]. Indeed the
expression of miR-29a, miR-29b-1, and miR-9 is significantly
decreased in Alzheimer’s disease and their decrease causes aberrant
increase of their target β-secretase-1 (BACE1), a protein account-
able for accumulation of Aβ in Alzheimer’s disease [100]. Besides
BACE1, the expression of amyloid precursor protein is repressed
by the members of the miR-20a family (miR-20a, miR-17-5p, and
miR-106b) and this miRNA pathway appears to be compromised
in Alzheimer’s disease because miR-106b is substantially reduced
in sporadic Alzheimer’s disease [101].
2.3.3 miRNAs As in many other tissues miRNAs mediate cell differentiation and
in Respiratory Disease maintain homeostasis in differentiated cells in the respiratory sys-
tem [102]. miRNA expression undergoes profound changes dur-
ing lung development and the Dicer null mice are not viable due
to impaired lung growth that is caused by deficiency in production
of mature miRNAs globally due to deletion of Dicer [103, 104].
Moreover, expression of the miR-17~92 cluster progressively
declines during lung development and forced expression of the
cluster results in abnormal lung development that was character-
ized by continued proliferation and impaired differentiation of epi-
thelial cells [105].
Profound alteration in miRNA expression profile has been
observed in asthma and asthma undergoing steroid therapy [106,
107]. More importantly the altered miRNA expression profile
observed in asthma appears to be largely driven by IL-13, a key
pathogenic cytokine in asthma because the miRNA profile in
asthma can be recapitulated by exposing lung epithelial cells to
IL-13 [107]. T cells are important orchestrators of the chronic
inflammatory response in asthma. In the circulating CD4+ and
CD8+ T cells collected from the patients with severe asthma the
expression of miR-146a and miR-146b are substantially downreg-
ulated and such downregulation potentially contributes to greater
T-cell activation in severe asthma because these two miRNAs
inhibit the immune response [108, 109].
8 Min Xue et al.
Idiopathic pulmonary fibrosis is a deadly lung disease featuring

excessive production and deposition of extracellular matrix com-
ponents by fibroblasts and myofibroblasts in the lung interstitium.
miRNA expression profiling of human lung samples, isolated lung
cells, and mouse models of idiopathic pulmonary fibrosis have
revealed profound dysregulation of miRNA that includes let-7d,
miR-21, and miR-29 [110–114]. More importantly reversing the
expression pattern of let-7d and miR-21 observed in pulmonary
fibrosis can attenuate pulmonary fibrosis in mice, suggesting that
these miRNAs mediate fibrosis in the lung [110–114]. It is note-
worthy that miR-29 represses expression of a host of extracellular
matrix proteins and has been implicated as a key regulator in
fibrotic diseases in other organs as well [115].
Chronic obstructive pulmonary disease (COPD) is caused pre-
dominantly by long-term exposure to cigarette smoke and charac-
teristic of destruction of the lung parenchyma (emphysema) and
reduced lung function. A miRNA expression profiling of lung tis-
sues collected from smokers with and without COPD has revealed
a panel of 70 miRNAs that are differentially expressed between
smokers with and without COPD [116]. This panel is enriched
with the miRNAs linked to the pathways that underlie the patho-
genesis of COPD, such as the TGF-β, Wnt, and focal adhesion
pathways [116]. For instance upregulated expression of miR-15b
is observed only in the smoker with COPD and correlated with a
decrease of its validated target SMAD7, a well-established inhibitor
of the TGF-β pathway [116]. In two other in-depth studies
reduced miR-146a expression is linked to increased expression of
PGE2 due to loss of miR-146a-mediated repression of COX-2 and
reduced expression of miR-1 is linked to the muscle weakness
observed in COPD [117, 118].
3 Functions of lncRNAs and Human Disease
lncRNA is a heterogenous family that is represented by long inter-

genic RNAs (defined by position), circular RNAs (circRNA,
defined by structure), competing endogenous RNA (ceRNA,
defined as functions), antisense RNAs (defined by orientation of
transcription), etc. According to the Ensembl human genome
annotation (GRch38, version 23) 27,817 lncRNAs are transcribed
from 15,931 gene loci [119]. lncRNAs are of absent or limited
protein coding potential. However, increasing number of genes
can dually produce peptides/proteins and lncRNAs. For example,
the RNA and proteins products of the steroid receptor RNA acti-
vator gene are simultaneously produced and the RNA product
function as a scaffold for formation of several ribonucleoprotein
complexes [120]. Similar to mRNA, most lncRNAs are transcribed
by RNA polymerase II, 5′-capped, 3′-polyadenylated, and spliced
into various isoforms although they tend to have fewer exons than
mRNAs [1].
The importance of lncRNA genes are revealed by their prox-
imity to developmental regulators in the genome, enrichment of
tissue-specific and developmental stage-specific expression pat-
terns, and frequent association with genetic traits [121]. lncRNAs
regulate a myriad of molecular and cellular processes, such as
chromatin remodeling and RNA splicing [122–126]. In the fol-
lowing sections we discuss the functions of lncRNAs and their role
in human disease.
3.1 Functions of A large number of lncRNAs can recruit chromatin remodeling

lncRNAs complexes to a specific set of genes to activate or repress gene
expression [127–133]. As many as 20% of lncRNAs expressed in a
3.1.1 Regulation of
given cell associate with chromatin remodeling complexes and
Epigenetic Modifications
lncRNAs are commonly bound by multiple chromatin remodeling
proteins [134]. One of the best-characterized interactions between
lncRNAs and chromatin remodeling complexes is lncRNA-
mediated recruitment of polycomb repressive complex 2 (PRC2)
that catalyzes trimethylation of histone H3 lysine 27 (H3K27me3),
a histone code for transcriptional repression [135].
lncRNAs can act in cis to recruit chromatin remodeling com-
plexes to regulate gene expression, which is well-characterized in
X-chromosome inactivation by the lncRNA X-inactive-specific
transcript (XIST) [136, 137]. In mammalian females, the majority
of genes on one of the two X-chromosomes in each cell are silenced.
During female development, XIST is transcribed from the
X-chromosome that is destined to become inactivated in each cell.
XIST then coats the regions of the chromosome that is to be
silenced, which results in formation of “XIST clouds” and recruit-
ment of PRC2 to the XIST-coated region for gene silencing [138].
On the other hand, lncRNAs can act in trans to recruit PRC2
to repress gene expression. As a paradigm of such mechanism, the
lncRNA HOX antisense intergenic RNA (HOTAIR) is transcribed
from the locus between HOXC11 and HOXC12 on chromosome
12 and repress the HOXD gene cluster on chromosome 2 via
recruitment of PRC2 [129]. As demonstrated by chromatin isola-
tion by RNA purification HOTAIR preferentially occupies a
GA-rich DNA motif to recruit PRC2 and nucleate broad domains
of H3K27me3 [139].
lncRNAs can regulate another important epigenetic code,
DNA methylation, a dynamic and reversible process that governs
gene expression during development and disease. In general cyto-
sine methylation in a CpG island located in a gene promoter marks
a gene for repression. An antisense lncRNA named TCF21 anti-
sense RNA inducing demethylation (TARID) activates TCF21
expression by inducing promoter demethylation [140]. TARID
recruits growth arrest and DNA-damage-inducible-α (GADD45A)
10 Min Xue et al.
to the TCF21 promoter. GADD45A, a regulator of DNA demeth-

ylation, in turn recruits thymine-DNA glycosylase for base excision
repair-mediated demethylation in the TCF21 promoter [140]. In
summary lncRNA can regulate the epigenetic codes through phys-
ical interaction with chromatin or nucleotide modifiers.
3.1.2 Regulation of RNA Besides regulation of epigenetic codes a large number of lncRNAs
Splicing regulate RNA splicing. For instance the lncRNA metastasis-
associated lung adenocarcinoma transcript 1 (MALAT1) regulates
alternative splicing through its interaction with the serine/arginine-
rich (SR) family of nuclear phosphoproteins, a key component of
the splicing machinery [141, 142]. MALAT1 is required for appro-
priate splicing because depletion of MALAT1 results in increase of
mislocalized and unphosphorylated SR proteins as well as increase
of exon inclusion events [142]. It is proposed that MALAT1 serves
as a structural docking site for accumulation and assembly of spe-
cific splicing factors, such as phosphorylated SR proteins and this
process is essential for efficient splicing [141].
3.1.3 Regulation Another step of a RNA life cycle regulated by lncRNAs is mRNA
of mRNA Decay decay as illustrated in staufen-1-mediated mRNA degradation
[143]. Staufen-1 binds to translationally active mRNAs via imper-
fect base-pairing between one Alu element in the 3′ UTR of a
staufen-1 target and another Alu element in a cytoplasmic, polyad-
enylated long noncoding RNA (lncRNA) [143]. Formation of the
mRNA-lncRNA-staufen-1 hetero triplex leads to degradation of
the staufen-1-targeted mRNAs [143]. It is noteworthy that this
process assigns a novel function to Alu, an ancient DNA repetitive
element, which is echoed in a novel function of another repetitive
element SINEB2 as discussed below.
3.1.4 Regulation lncRNAs can regulate the final step of an mRNA life cycle, transla-
of mRNA Translation tion, through base-pairing with the targeted mRNAs and forma-
tion of this RNA-RNA duplex that in turn modulates the interaction
between the translated mRNAs and ribosomes [144, 145]. The
antisense lncRNAs that complement the targeted mRNAs at the 5′
end promote association of polysomes with the targeted mRNAs.
A nuclear-enriched lncRNA antisense to mouse ubiquitin carboxy-
terminal hydrolase L1 (Uchl1) can increase UCHL1 mRNA trans-
lation, which requires the presence of a 5′ overlapping sequence
and an embedded inverted SINEB2 element [145]. On the con-
trary, lincRNA-p21 can associate with JUNB mRNA and selec-
tively reduce its translation when lincRNA-p21 is released from
HuR, a RNA-binding protein that binds to and limits the avail-
ability of lincRNA-p21 for targeting JUNB [144].
3.1.5 Molecular Scaffold lncRNAs can serve as molecular scaffolds for assembly and posi-
for Structural/Functional tioning of structural or functional complexes so that the lncRNA
Complexes containing complexes can function in an appropriate spatial and
temporal manner [134, 146, 147]. HOTAIR provides a paradigm

of how lncRNAs act as a modular scaffold. HOTAIR interacts with
PRC2 and lysine-specific demethylase 1 (LSD1) corepressor com-
plex to silence the HOXD locus in trans [148]. Assembly and posi-
tioning of a transcriptional corepressor complex containing PRC2
and LSD1 on a HOTAIR bound gene promoter can efficiently
coordinate histone codes for gene silencing via PCR2-mediated
addition of repression code H3K27me3 and LSD1-mediated
removal of activation code H3K4me3. Such coordination is
achieved through scaffolding by HOTAIR in that HOTAIR binds
to PRC2 via its 5′ terminus and to LSD1 via its 3′ terminus [148].
3.2 lncRNAs lncRNAs dictates fundamental cellular and developmental pro-

and Human Disease cesses and thereby underlie pathogenesis of a broad range of
human diseases. Aside from their well-established roles in cancer,
lncRNAs are central to fragile X syndrome, neurodegenerative dis-
ease, respiratory disease, etc. [149–154]. In this section we review
recent advances on the role of lncRNAs in cancer, neurodegenera-
tive disease, and respiratory disease.
3.2.1 lncRNAs in Cancer lncRNAs have emerged as novel master regulators of initiation,
progression, and response to therapy in a wide variety of solid
tumors and hematological malignancies [155]. Hundreds of
IncRNAs are differentially expressed between tumor tissues and
paired adjacent nontumor tissues in various types of cancer [156–
164]. lncRNAs can act as oncogenes or tumor suppressors to regu-
late cancer biology via diverse molecular mechanisms [141, 158,
159, 165–167].
One of the classical and versatile cancer-associated lncRNAs is
MALAT1. Elevated expression of MALAT1 has been reported in a
broad range of cancers, including lung cancer and breast cancer
[168–184]. Moreover, genetic alterations in MALAT1, such as
multiple mutations and deletions within the SRSF1-binding sites
are associated with poor patient outcome in breast cancer [185].
In colorectal cancer and osteosarcoma, MALAT1 promotes tumor
growth and metastasis by binding to a multifunctional RNA-
binding protein, PSF via a motif in its 3′region [186, 187].
Depletion of MALAT1 results in defective alternative splicing of a
subset of transcripts that are involved in cancer such as tissue factor
and endoglin [188]. Besides regulation of splicing of the cancer-
associated genes MALAT1 regulates expression of the cancer asso-
ciated genes via epigenetic mechanisms. For example, MALAT1
binds to polycomb group proteins to facilitate assembly of multiple
corepressors/coactivators and thereby mediates activation of the
growth-control gene program for proliferation [189]. MALAT1
also associates with PRC2 and alters the expression of N-cadherin
and E-cadherin to promote EMT in bladder cancer cells [175].
Besides its potential as a biomarker, MALAT1 is an appealing
12 Min Xue et al.
therapeutic target for cancer metastasis because deletion or inhibi-

tion of MALAT1 reduces tumor growth and metastasis of human
lung cancer cells in xenografted mice [187].
Another prime example of oncogenic lncRNAs is HOTAIR
[190, 191]. HOTAIR is elevated in various cancers including
breast cancer, lung cancer, colorectal cancer, and prostate cancer
[159, 192–194]. Elevated HOTAIR expression is a powerful pre-
dictor of metastasis and poor survival [159]. The paradigm of
HOTAIR’s functions in cancer is that increased amount of
HOTAIR reprograms global gene occupancy of PRC2, which
results in de novo repression of hundreds of new target genes to
promote invasion and metastasis [159]. HOTAIR mediates cancer
cells’ resistance to chemotherapy because elevated expression of
HOTAIR is correlated with tamoxifen resistance in breast cancer
and its overexpression promotes ligand-independent proliferative
activities of estrogen receptor [195].
Similar to miRNAs lncRNAs can regulate the hallmarks of can-
cer via diverse mechanisms as illustrated in regulation of apoptosis
and proliferation by the lncRNA growth arrest-specific transcript 5
(GAS5). GAS5 is induced upon growth arrest due to lack of nutri-
ents or growth factors and overexpression of GAS5 induces growth
arrest and apoptosis in cancer cells [196]. Acting as molecular
decoy through its binding to the DNA-binding domain of gluco-
corticoid receptor GAS5 sequesters glucocorticoid receptor and
thereby suppresses glucocorticoid-activated genes, particularly the
inhibitors of apoptosis [196]. Another example of lncRNA-
mediated control of cell cycle control is lincRNA-p21 whose
expression is induced by p53 upon DNA damage [166]. Upon
induction by p53 lincRNA-p21 interacts with ribonucleoprotein K
and act in trans to recruit ribonucleoprotein K to repress a host of
p53 targeted genes, particularly the genes that interfere with the
apoptotic response to DNA damage. On the other hand, lincRNA-
p21 can function in cis to activate expression of its neighboring
gene, particularly p21, an essential mediator of p53-dependent
growth arrest response to DNA damage [197].
Given their pivotal role in cancer biology lncRNAs have
emerged as promising targets for diagnosis and therapy of cancer.
Some lncRNAs are potential biomarkers of a broad range of can-
cer, such as HOTAIR that is upregulated in the majority of can-
cers investigated so far [191]. More importantly elevated
expression of HOTAIR and MALAT1 is valuable in prognosis
because their aberrant expression correlates significantly with
metastasis and poor overall survival in breast, lung, and colorectal
cancers [160, 191, 198, 199]. On the other hand, some lncRNAs
are dysregulated in cancer in a tissue type-specific manner. For
instance the lncRNA prostate cancer antigen 3 (PCA3) is upregu-
lated specifically in prostate tumor tissue over normal/nonmalig-
nant tissue [200, 201].
Similar to miRNAs altered expression of lncRNAs in various

body fluids is often congruent to their dysregulated expression in
the tumor tissues. Thus acquisition of lncRNA based biomarkers in
body fluids is convenient, minimally invasive, and cost-effective
relative to conventional tissue biopsies. Particularly the circulating
lncRNAs exist in exosomes released by cancer cells because the
lncRNAs packaged into exosomes appear to be tightly controlled
and thus provide pivotal information of their parental cancer cells
that otherwise requires conventional biopsies to obtain [202, 203].
One of the most explored methods to inhibit upregulated
oncogenic lncRNAs is RNA interference. siRNAs targeting
lncRNAs via base-pairing have yielded promising efficiency in
reducing lncRNA expression and cancer growth/metastasis as
observed in targeting HOTAIR in breast cancer cells [159, 204].
Another base-pairing approach is using longer antisense oligonucle-
otides to promote degradation of the targeted lncRNA by RNase H
that was successfully applied to target MALAT1 in lung cancer cells
[168]. On the other hand, the expression of the tumor suppressive
lncRNAs may be enforced/introduced by delivery of an lncRNA
transgene. Because lncRNAs function through physical interactions
with protein partners in normal and cancer contexts one ideal
approach to specifically interfere the lncRNAs’ functions in cancer
is to disrupt the cancer-specific interaction between lncRNAs and
their protein partners. This approach has been attempted in a feasi-
bility test that successfully identified the compounds that can dis-
rupt the interaction between HOTAIR and PRC2 [205].
3.2.2 lncRNAs lncRNAs have emerged as orchestrators of gene regulatory net-

in Neurodegenerative works in the nervous system. Hundreds of lncRNAs exhibit tempo-
Disease ral and spatial patterns of expression in the nervous system, which
suggest that they play key roles in development and normal func-
tions of the nervous system [206]. As validated by a profiling and
functional analysis of lncRNAs in human embryonic stem cells effi-
cient neuronal differentiation of embryonic stem cells requires sev-
eral lncRNAs, such as lncRNA_N1 (AK124684) and lncRNA_N2
(AK091713) [207]. We review the role of lncRNAs in two neuro-
degenerative diseases, Alzheimer’s disease and Parkinson’s disease.
One salient example of lncRNAs linked to pathogenesis of
Alzheimer’s disease is the lncRNA named antisense transcript of
β-secretase-1 (BACE1-AS). BACE1 is believed to be the culprit of
accumulation of β-amyloid and the consequent formation of amy-
loid plaques that are pathological hallmarks of Alzheimer’s dis-
ease. BACE1-AS can increase the mRNA levels of BACE1 by
duplexing with and stabilizing the BACE1 mRNA [149]. More
importantly BACE1-AS is elevated in the brains of patients with
Alzheimer’s disease, suggesting that BACE1-AS mediates upregu-
lated expression of BACE1 in Alzheimer’s disease [208]. The
amount of BACE-1AS in the brains of patients with Alzheimer’s
14 Min Xue et al.
is proportional to the severity of dementia [149]. Another lncRNA

linked to Alzheimer’s disease belongs to a family of the brain cyto-
plasmic (BC) lncRNAs. The lncRNA BC200 is transported to
dendritic processes via ribonucleoprotein particles and regulate
gene expression at the translational level [209]. BC200 declines in
the frontal cortex of normal aging brain, but increases in
Alzheimer’s disease, and its increase is congruent to the severity of
dementia [210].
In Parkinson’s disease, aberrant expression of PTEN induced
kinase 1 (PINK1) leads to abnormal mitochondrial morphology,
impaired dopamine release, and motor deficits [211]. The lncRNA
natural antisense RNA of PINK1 (naPINK1) is transcribed as an
antisense transcript from the PINK1 locus and stabilizes the expres-
sion of a PINK1 splice variant (svPINK1) containing a domain
homologous to the C-terminus regulatory domain of PINK1
[212]. Silencing of naPINK1 results in decrease of svPINK1 in
neurons, which suggests that naPINK1 and svPINK1 are concor-
dantly regulated during impairment of mitochondrial biogenesis
related to Parkinson’s disease [212].
3.2.3 lncRNAs Hundreds of lncRNAs are expressed in a developmental stage-

in Respiratory Disease specific and cell type-specific manner in the mouse lung [213].
Moreover, the lncRNA expressing genomic loci are enriched with
the binding sites for the established master transcriptional regula-
tors of lung development, such as serum response factor, forkhead
box, and SP1. In particular, two lncRNAs, NANCI and LL34,
regulate expression of the genes that govern the key steps in dif-
ferentiation and development of airway epithelial cells [213].
These findings implicate a critical role of lncRNAs in lung develop-
ment, function, and disease.
The importance of lncRNAs in respiratory disease is high-
lighted in characterization of the deletion of the locus harboring
several lncRNAs in a rare lethal neonatal lung disorder alveolar
capillary dysplasia with misalignment of pulmonary veins (ACD/
MPV) [214]. The lung-abundant 16q24.1 lncRNAs transcribed
from the deleted locus of ACD/MPV may contribute to long-
range regulation of FOXF1 by GLI2 and other transcription fac-
tors via chromatin looping [214]. Loss of those lncRNAs due to
deletion results in loss of FOXF1 expression as well as consequent
vascular pathology observed in ACD/MPV. It is conceivable that
similarly dysregulated lncRNA expression and function occur in
pulmonary vascular remodeling in pulmonary arterial hyperten-
sion and asthma. Indeed in asthma and COPD inhibition of
MALAT1 appears to be a promising approach to attenuate occlu-
sive lesions in pulmonary arterial hypertension, inhibit airway epi-
thelial cell proliferation, and reduce obstructive remodeling of the
airways [215].
4 Regulation of miRNAs by lncRNAs
A new frontier in the noncoding RNA world is the cross talk

between miRNAs and lncRNAs [216]. Recent studies have dis-
covered and characterized naturally occurring microRNA sponges,
termed competing endogenous RNAs (ceRNAs) [217]. These
ceRNAs consist of a variety of RNA species that include protein-
coding mRNAs, pseudogenes, and lncRNAs (including cir-
cRNAs). We focus on regulation of miRNAs by lncRNAs.
One of the well-charaterized ceRNAs is linc-RoR that is abun-
dantly expressed in human embryonic stem cells [218]. linc-RoR
sequesters miR-145 and thus protects OCT4, SOX2, and NANOG
from miR-145-mediated repression [218]. The linc-ROR-
mediated interference of miR-145 is essential to renewal of embry-
onic stem cells [218]. In a similar fashion HOTAIR antagonizes
several tumor suppressive miRNAs. In gastric cancer cells,
HOTAIR acts as a ceRNA to trap miR-331-3p through a comple-
mentary target site in its sixth exon and consequently increases the
expression of the miR-331-3p-targeted oncogene HER2 [219].
In gall bladder cancer, HOTAIR’s oncogenic activity requires its
binding to and titration of miR-130a through a target site in its
sixth exon [220]. Interestingly the interaction between HOTAIR
and miR-130a is reciprocal because miR-130a represses the
expression of HOTAIR in a target site-dependent manner [220].
The oncogenic lncRNA H19 acts as a ceRNA of two tumor sup-
pressive miRNAs, miR-141 and let-7 and thus promotes the pro-
liferative and invasive phenotypes of cancer cells [221, 222].
Besides cancer ceRNAs play a critical role in normal physiology.
For instance linc-MD1 is a ceRNA that mediates skeletal muscle
differentiation by titrating away miR-133 and miR-135 from their
targets MAML1 and MEF2C mRNAs [223]. Decreased expres-
sion of linc-MD1 is believed to mediate pathogenesis of Duchenne
muscular dystrophy, a devastating muscle degenerative disease due
to uncontrolled repression of MAML1 and MEF2C by miR-133
and miR-135 [223].
circRNAs are structurally distinct in that they form a cova-
lently closed continuous loop in which the 3′ and 5′ ends that are
normally exposed in an linear RNA molecule are joined together
in circRNAs. Several circRNAs containing multiple target sites of
an individual microRNA have been characterized, which indicate
that circRNAs can efficiently sequester microRNAs [224]. For
instance, the circRNA sponge for miR-7, ciRS-7, contains dozens
of miR-7 target sites and is enriched in the human and mouse
brain [225]. More importantly, ciRS-7 regulates brain develop-
ment by titrating miR-7 [225].
16 Min Xue et al.
5 Conclusions
miRNAs and lncRNAs have emerged as central players in funda-

mental cellular processes, development, and pathogenesis of
human disease. The complexity, flexibility, and versatility of the
structures and functions of miRNAs and lncRNAs demand inte-
gration of experimental and bioinformatic tools to acquire suffi-
cient knowledge for applications of these noncoding RNAs in
clinical care.
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Chapter 2
MicroRNA Expression: Protein Participants in MicroRNA

Regulation
Valeria M. King and Glen M. Borchert
Abstract
MiRNAs are ~20 nt small RNAs that regulate networks of proteins using a seed region of nucleotides 2–8
to complement the 3′ UTR of target mRNAs. The biogenesis and function of miRNAs as translational
repressors is facilitated by protein counterparts that process primary and precursor miRNAs to maturity
(Drosha/DCGR8 and Dicer/TRBP respectively) and incorporate miRNAs into the protein complex
RISC to recognize and repress target mRNAs (RISC proteins: Ago/TRBP1/TRBP2/DICER). Similarly,
siRNAs through comparable mechanisms are loaded into the protein complex RITS to heterochromatin
formation of DNA and suppress transcription of particular genes. MiRNAs are also regulated themselves
through many different pathways including transcriptional regulation, post-transcriptional RNA editing,
and RNA tailing. Dysregulation of miRNAs and the protein participants that mature them are implicated
in the development of a number of diseases, tumorigenesis, and arrested development of embryonic cells.
In this chapter, we will explore the biosynthesis, function, and regulation of miRNAs.
Key words Dicer, Drosha, miRNA, mRNA, Protein, RISC, Regulation
1 MicroRNA Production and Activity
MicroRNAs are small noncoding RNAs around 22 nucleotides in

length that are involved in the regulation of mRNAs in the cyto-
plasm via inducing translational repression or message degradation
[1]. MiRNAs constitute a broad regulatory network with one
miRNA potentially regulating dozens of distinct mRNAs. These
regulatory networks control levels of specific proteins and other
RNAs like long noncoding RNAs (lncRNAs) in cells. MiRNA mis-
regulation is implicated in cancer, a myriad of other illnesses, and
abnormal development [2–4]. The first miRNA was described in
1993 and was initially thought to be a novel molecular species
unique to Caenorhabditis elegans [5]. In 2001, however, nearly 10
years after their initial discovery, miRNAs were found to occur in
several different species including humans [6]. Since that time,
novel miRNA discovery has proceeded at a marked rate, and by
Jingshan Huang et al. (eds.), Bioinformatics in MicroRNA Research, Methods in Molecular Biology, vol. 1617,
DOI 10.1007/978-1-4939-7046-9_2, © Springer Science+Business Media LLC 2017
27
28 Valeria M. King and Glen M. Borchert
2015, MiRBase.org [7] has detailed significant evidence support-

ing the expressions of over 2500 unique human miRNAs and well
over 28,000 unique miRNAs across species.
1.1 MiRNA MiRNAs are transcribed from the genome by RNA Polymerase II
Processing (Pol II) or Pol III [1]. Transcription results in an initial transcript
(called a primary miRNA or pri-miRNA) of variable length con-
taining an unprocessed hairpin [8]. The pri-miRNA is next pro-
cessed by a ribonuclease protein complex including DROSHA,
which targets and cleaves the flanking ends of the hairpin, and
DCGR8 that stabilizes the complex on the pri-miRNA. DROSHA
processing yields an ~70–100 nt long stem loop called a precursor
miRNA or pre-miRNA [9].
Following excision, the pre-miRNA stem loop is transported
out of the nucleus and into the cytoplasm via the transport protein
exportin-5 using an active transport mechanism with GTP. Once
in the cytoplasm, the pre-miRNA is targeted by another ribonucle-
ase, DICER, which cleaves the molecule further by removing the
loop portion of the hairpin and leaving an intermediate duplex
which consists of the mature miRNA and a semi-complementary
sequence referred to as the passenger strand. The intermediate
duplex, which is ~22 base pairs in length, is then loaded into an
Argonaute (Ago) protein, and the passenger strand discarded [1]
(see Fig. 1).
1.2 Genomic Loci MiRNAs can be separated into two broad categories depending on
their position in the genome: canonical and noncanonical [1].
Canonical miRNAs are those that are found in intergenic regions
and are cleaved by Drosha/DCGR1 to form the precursor miRNA
(pre-miRNA) [1, 2]. Noncanonical miRNAs are mitrons or pre-
miRNAs that are cleaved from intron sequences using splicing
instead of Drosha.
While the evolutionary origin of miRNAs is still largely
unknown, significant evidence suggests that miRNAs and their
regulatory networks arose from the insertion of transposable ele-
ments in the genome [10]. Importantly, the ability of miRNAs to
regulate multiple distinct genes may have directly arisen as a conse-
quence of transposons inserting themselves into the UTRs of pro-
tein coding genes. Since miRNAs target mRNAs through sequence
complementarity, the ability of a miRNA to identify and target a
specific mRNA may well be due to a common molecular origin
shared by a miRNA locus and its mRNA target sites [10–12] (see
Fig. 2).
1.3 Translational The mature miRNA in conjunction with the Ago protein is called
Repression and Signal an RNA-induced silencing complex or RISC. MiRNAs function as
Degradation protein level regulators by binding target mRNAs and inducing
transcriptional repression and in some instances complete signal
MicroRNA Expression: Protein Participants in MicroRNA Regulation 29
Fig. 1 Canonical and noncanonical miRNA maturation pathways. Cartoon illustrating the transcription of a
canonical miRNA, Drosha/DGCR8 processing of the primary hairpin, and the export of the resulting hairpin to
the cytoplasm mediated by exportin-5 and GTP. Once in the cytoplasm, the hairpin is recognized and bound by
DICER which cleaves the loop off of the stem loop and leaves a double-stranded intermediate duplex. The
mature strand bound to the passenger strand is then loaded into an Ago protein complex called RISC. RISC
transports the miRNA to a prospective mRNA target which the miRNA recognizes and binds. Once the RISC
complex is bound to an mRNA, translation of the mRNA cannot occur and is repressed
degradation. Included in a mature miRNA is a ~7 nt sequence (nts

2–8) called the miRNA seed that perfectly complements a specific
region of a mRNA called a seed match usually found in the 3′
UTR. A miRNA seed binds a corresponding seed match in a
mRNA, and RISC inhibits its translation. RISC localizes mRNAs
that are under transcriptional repression to p-bodies where the
mRNA is eventually degraded or released back into the cytoplasm
for translation [4]. If the seed is highly complementary to the seed
match, the Ago2 protein associated in RISC cleaves the mRNA
and results in signal degradation (see Fig. 3).
1.4 RISC The regulation of mRNAs by miRNAs is accomplished by the

RNA-induced silencing complex, or RISC. RISC consists of sev-
eral different proteins, is between 200 and 500 kDa and exhibits
Fig. 2 MiRNA regulatory networks arising from transposable elements. Cartoon depicting transposable line
elements being transcribed and inserted into the genome in multiple locations including in the untranslated
region of a protein-coding gene. To produce a miRNA hairpin, two line elements are inserted in the genome
juxtaposed to each other on different strands. MiRNAs are able to recognize target mRNA seed matches
because they each share part of a line element sequence
ribonuclease activity [13]. MRNAs are incorporated into the RISC

complex when targeted by miRNAs. AGO proteins in RISC cleave
mRNAs that are highly complementary to the incorporated
miRNA, whereas mRNAs that are mostly imperfectly bound to the
miRNA are silenced by translation inhibition. The best described
protein subunits of RISC are the RNases Dicer, Ago 1 and 2. Ago
1 and 2 serve as the central components of RISC and are respon-
sible for translational repression and cleavage/degradation [14].
Also included in RISC are TAR RNA binding proteins, or TARBPs,
which comes in two isoforms, TARBP1 and 2. TARBP proteins
contain domains that bind double-stranded RNA [15]. TARBP1
functions as a methyltransferase that recruits an Ago protein into
RISC [16]. Additionally, TARBP2 loads the miRNA into RISC
and exhibits a double-stranded RNA (dsRNA) binding site, which
holds the miRNA inside RISC [17, 18].
In addition to loading RNAs into RISC, TRBPs also stabilize
Dicer during pre-miRNA processing. After an incorporated miRNA
binds to an mRNA, the Ago protein either cleaves the mRNA for
degradation, which is usually associated with Ago 2, or the protein
Fig. 3 Translational regulation through seed matching. Cartoon showing the seed region of a mature miRNA
incorporated into RISC recognizing and binding to the seed match region of an mRNA. RISC takes the mRNA to
the p-body region where it represses translation or cleaves the mRNA for degradation
in conjunction with RISC prevents translation from occurring until

the message is degraded or the message is released by RISC through
stress-induced pathways and is recycled [19] (see Fig. 3).
1.5 SiRNAs and RITS SiRNAs, or small interfering RNAs, are noncoding RNAs with
comparable size and function to miRNAs. SiRNAs differ from
miRNAs in several aspects including the pathways from transcrip-
tion to maturity, and in that while miRNAs generally regulate
mRNA networks, siRNAs typically regulate a specific target gene
[17]. RITS, or RNA-induced initiation of transcriptional silencing,
is a complex of proteins in conjunction with a mature siRNA that
inhibits the transcription of specific genes by triggering hetero-
chromatin assembly in centromeric regions.
SiRNA and RITS complexes have been experimentally charac-
terized in fission yeast. In fission yeast the RITS complex consists
of Ago1; Chp1, which is a hetero-chromatin-associated protein;
and Tas3, a novel protein that is necessary for H3-K9 methylation
[20]. This protein complex, in conjunction with a mature siRNA,
targets specific regions of DNA and silences them using methyla-
tion and heterochromatin biogenesis [21]. Upon being loaded
Fig. 4 DNA methylation facilitated by RITS and siRNA is a cartoon depicting dsRNA or double-stranded RNA
being cleaved by Dicer and matured into an siRNA or small interfering RNA. RITS is composed of at least three
protein components including Ago1, Chp1, and Tas3. The RITS protein complex, in conjunction with the siRNA,
binds to a centromeric region of DNA specified by the siRNA and enables methylation of the H3 histone by Clr4,
an H3 methyltransferase
into Ago1, a siRNA will bind a complementary centromeric region

of DNA in complex with the RITS proteins. Then K9 methylation
of the H3 histone is initiated by Clr4 protein, a histone H3 meth-
yltransferase [22]. In response to this methylation, targeted DNA
coils tightly around its associated histones thereby preventing tran-
scription of the region (see Fig. 4).
2 MiRNA Regulation
Importantly, miRNAs are themselves regulated through several

different mechanisms such as transcriptional regulations, single
nucleotide polymorphisms (SNPs), RNA editing, miRNA tailing,
and miRNA degradation [23]. MiRNA regulation can alter miRNA
expressions and protein targets, affect miRNA dosing and miRNA
proliferation, and induce miRNA degradation.
2.1 Regulation Transcriptional regulation of miRNAs is perhaps the most well-

of MicroRNA understood mechanism by which to regulate miRNA biogenesis
Transcription [24]. MiRNA locus methylation is the untemplated addition of
methyl groups to a region of DNA in order to encourage tight

heterochromatin folding of DNA that prevents transcription.
MiRNAs can be down regulated when regions in the DNA that
code for the miRNA and regions that allow the miRNA to be tran-
scribed such as a promoter or transcription factor are silenced by
gene inaccessibility [25]. Hypomethylation plays a role in up-
regulated levels of miRNAs in the cell.
Regions that are normally inaccessible to transcription can be
“opened up” by mechanisms that are as yet not fully understood.
Hepatocellular carcinoma (HCC) is associated with the dysregula-
tion of miRNAs by hypermethylating regions of the DNA which
include tumor-suppressing miRNAs and hypomethylating regions
that are normally constitutively transcribed and causes the up-
regulation of miRNAs that can promote tumor growth [26].
Additionally, transcription can also be affected by levels of par-
ticular proteins (typically transcription factors) in the cell. For
instance, mir-145 has been shown to produce an apoptotic effect
in cells following an activation of TP53, a tumor suppressor. The
production of TP53 also stimulates the transcription of miRNA-
145 creating an apoptosis-promoting loop. Conversely, miRNA-
145 under-expression is observed in a variety of cancers including
breast, colon, and lung cancers [27].
Further, transcriptional regulation of miRNAs has been shown
to play a major role in embryonic stem cell (ES cell) differentiation
[28]. Four transcription factors have been implicated in regulating
miRNA levels in the cell to induce differentiation in mice: Oct4,
Sox2, Nanog, and Tcf3. Using CHIP-seq data and intensive
miRNA promoter mapping, Marson et al. were able to show that
the transcription factors bind to promoter regions that are respon-
sible for the transcription of at least 81 miRNA genes and inhibit
particular miRNAs from being transcribed [29]. This process
results in the shift of ES cells from pluripotency to specificity [30].
The transcription factors bind to the promoter regions of miRNA
genes and prevent the gene from being polymerized which in turn
results in increased expression of proteins that the targeted miRNA
regulates.
2.2 Single Nucleotide Single nucleotide polymorphisms or SNPs are areas in the genome
Polymorphisms where a single nucleotide can differ between individuals due to
typically benign mutations in the DNA sequence [31]. That said,
SNPs can drastically alter miRNA activity in the cell. A SNP in the
seed sequence of a miRNA can significantly alter its targets and
allow a certain protein to go uninhibited while another protein
becomes more stringently regulated. This can cause issues when
oncogenes, for example, are no longer being targeted to be a par-
ticular miRNA, or if tumor suppressor proteins are severely
repressed following the introduction of an SNP in a miRNA that
does not normally regulate the tumor suppressor gene [23]. SNPs
can also lead to miRNA regulation when it is not localized in the

seed region. SNPs in the passenger strand or pri-miRNA stem loop
can interfere with Drosha and DICER processing and inhibit the
production of a mature miRNA [32].
2.3 RNA Editing MiRNAs can also be regulated through RNA editing. A protein
called ADAR1 can convert adenosine molecules into inosines that
preferentially form base pairs with cytosines [33]. RNA editing may
affect pri-miRNAs, pre-miRNAs, and mature miRNA sequences,
and like SNPs, these edits can alter gene targets or decrease the
affinity for Drosha or DICER affecting miRNA processing [34].
Importantly, it is estimated that 16% of human pri-miRNAs are
edited by ADAR1 [23], suggesting that ADAR editing may well
provide a largely underappreciated layer of complexity in miRNA
biogenesis. Although miRNA editing can allow the production of
several unique miRNAs with differing targets to be produced from
a single genomic locus, the effects of miRNA editing remain largely
unexplored.
2.4 MiRNA Tailing RNA tailing is the post-transcriptional addition of nucleotides to

the 3′ end of RNA. Uridylation mainly occurs in pre- and pri-
miRNAs. For example, during embryonic stages, members of the
let-7 family are suppressed after transcription by LIN28A and its
paralogue LIN28B. These proteins bind to the terminal loop of pri-
let7 and pre-let-7 respectively, and prevent Drosha and Dicer pro-
cessing. LIN28 proteins then employ terminal uridylyl transferases
TUT4 and TUT7 to signal pre-let-7 for decay by inducing oliguri-
dylation [35, 36]. Next, DIS3L2 exonuclease targets the oligo-U
tail and degrades the miRNA. Conversely, when LIN28 is down
regulated in cells, TUT7, TUT4, and TUT2 stimulate monouri-
dylation of pre-let-7, which increases let-7 proliferation [37].
Another type of RNA tailing is adenylation, which primarily
occurs in mature miRNAs. Adenylation can result in either miRNA
stabilization or miRNA decay [38]. As examples, miRNA-122, a
hepatic miRNA, is frequently stabilized by adenylation, whereas
poxvirus polyadenylation polymerase targets host miRNAs and
adenylates them causing their degradation. It remains unclear
what causes the difference in response following miRNA polyad-
enylation [39].
2.5 MiRNA Mature miRNA degradation has been observed in several different
Degradation systems. Though it is unclear how nucleases specify targets, numer-
ous nucleases are suspected of actively degrading miRNAs in
humans [18], C. elegans [40], and mice [41]. The first reported
instance in which miRNAs were rapidly degraded was observed in
Arabidopsis thaliana, in which mature miRNAs were cleaved and
removed by an association of 3′–5′ exonucleases called small-RNA-
degrading nuclease [42].
Similarly, it has been shown that viruses destabilize specific

miRNAs by using their own RNA that contains a perfectly comple-
mentary sequence [43]. For example, T cells that are infected with
herpes virus experience a rapid decrease in miRNA-27 due to viral
noncoding RNA specifically binding and destabilizing miRNA-27
[44]. Also, mouse cytomegalovirus contains RNA that specifically
binds miRNA-27 and facilitates its degradation [45].
3 Concluding Remarks
Though miRNAs genes were almost entirely overlooked until the

turn of the millennium, miRNAs have now been shown to play an
integral part in the post-transcriptional regulation of many (if not
a majority of) protein genes. What is more, our understanding of
miRNAs and their functions as regulators continues to broaden
with significant new insights continuing to be described. For
example, miRNAs were recently shown to target not only mRNAs,
but also other noncoding RNAs such as long noncoding RNAs or
lncRNAs. Linc-MD1 is a lncRNA that is expressed during myo-
blast differentiation in muscle cells. MiRNA-133 and -135 down
regulate two transcription factors that stimulate muscle-specific
gene expression, MAML1 and MEF2C respectively. Linc-MD1
competes with these transcription factors to bind the miRNAs and
allow the transcription factors to initiate cell differentiation [46].
As another example, other small RNAs have now been shown to
behave like mature miRNAs. For example, many snoRNAs, or
small nucleolar RNAs, classically thought to simply chemically
modify other RNAs, have now been reported to undergo alternative
processing and behave like mature miRNAs. In a recent study, spe-
cific snoRNAs were found to be processed into miRNA-like frag-
ments and direct translational repression of target genes [47].
In conclusion, while we have learned a lot about miRNA pro-
duction and regulation in a very short time, our understanding of
these molecules is still in its infancy, and exciting new revelations
undoubtedly await.
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Mobile, AL, USA Jingshan Huang

1 MicroRNAs, Long Noncoding RNAs, and Their Functions

16 Machine Learning Techniques in Exploring MicroRNA Gene Discovery,

Ryan G. Benton • Department of Computer Science, University of South Alabama

Lijun Xie • Department of Nuclear Medicine, First Affiliated Hospital of Kunming

MicroRNAs, Long Noncoding RNAs, and Their Functions

Key words MicroRNA, Long noncoding RNA

Majority of the human genome is transcribed although only ~2%

2 Functions of miRNAs and Human Disease

miRNAs [22]. Bioinformatic tools such as TargetScan have been

Hallmarks of cancer Representative miRNAs

hosting locus in chronic lymphocytic leukemia [44]. Single nucle-

responses to chemotherapy and thus guide the choice of treat-

Alzheimer’s disease is the most common cause of dementia in

Idiopathic pulmonary fibrosis is a deadly lung disease featuring

3 Functions of lncRNAs and Human Disease

lncRNA is a heterogenous family that is represented by long inter-

3.1 Functions of A large number of lncRNAs can recruit chromatin remodeling

to the TCF21 promoter. GADD45A, a regulator of DNA demeth-

temporal manner [134, 146, 147]. HOTAIR provides a paradigm

3.2 lncRNAs lncRNAs dictates fundamental cellular and developmental pro-

therapeutic target for cancer metastasis because deletion or inhibi-

Similar to miRNAs altered expression of lncRNAs in various

3.2.2 lncRNAs lncRNAs have emerged as orchestrators of gene regulatory net-

is proportional to the severity of dementia [149]. Another lncRNA

3.2.3 lncRNAs Hundreds of lncRNAs are expressed in a developmental stage-­

4 Regulation of miRNAs by lncRNAs

A new frontier in the noncoding RNA world is the cross talk

miRNAs and lncRNAs have emerged as central players in funda-

1. Derrien T, Johnson R, Bussotti G, Tanzer 12. Laulagnier K, Motta C, Hamdi S, Roy S,

transcriptional up-regulation of miR-21 by gation and chemoresistance. J Biol Chem

168. Gutschner T, Hammerle M, Eissmann M, 179. Wang X, Li M, Wang Z, Han S, Tang X et al

190. Loewen G, Jayawickramarajah J, Zhuo Y, pressed in prostate cancer. Cancer Res

MicroRNA Expression: Protein Participants in MicroRNA

Key words Dicer, Drosha, miRNA, mRNA, Protein, RISC, Regulation

1 MicroRNA Production and Activity

MicroRNAs are small noncoding RNAs around 22 nucleotides in

2015, MiRBase.org [7] has detailed significant evidence support-

degradation. Included in a mature miRNA is a ~7 nt sequence (nts

1.4 RISC The regulation of mRNAs by miRNAs is accomplished by the

ribonuclease activity [13]. MRNAs are incorporated into the RISC

Mobile, AL, USA Jingshan Huang

3.2.3 lncRNAs Hundreds of lncRNAs are expressed in a developmental stage-

2.1 Regulation Transcriptional regulation of miRNAs is perhaps the most well-