Identification of gene clusters with phenotype-dependent expression with application to normal and premature ageing
Pages 377 - 383
Abstract
Background: Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging manifested at a very early age. Molecular basis of HGPS is not entirely clear, although there are some known and other presumed overlaps with normal aging process. Comparative investigation of biological processes associated with HGPS and normal aging may reveal common and distinctive pathways underlying these two conditions.
Results: To investigate transcriptome changes through aging we have performed RNA-seq profiling in fibroblast cell cultures at three different cellular ages as measured by number of passages through culture growth, both from HGPS patients and matched normal samples. We then developed a novel iterative multiple regression approach that leverages co-expressed gene clusters to identify gene clusters whose expression changes significantly with age and/or disease state. We establish the robustness of our approach. Finally, we perform a comparative investigation of biological processes underlying normal aging and HGPS.
Conclusion: Based on an iterative multiple regression approach applied to novel RNA-seq data in HGPS and aging our results recapitulate the previously known processes underlying aging while at the same time suggests numerous unique processes underlying aging and HGPS.
References
[1]
Merideth, M.A., et al., Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med, 2008. 358(6): p. 592--604.
[2]
Eriksson, M., et al., Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 2003. 423(6937): p. 293--8.
[3]
Zhang, H., J.E. Kieckhaefer, and K. Cao, Mouse models of laminopathies. Aging Cell, 2013. 12(1): p. 2--10.
[4]
Gordon, L.B., K. Cao, and F.S. Collins, Progeria: translational insights from cell biology. J Cell Biol, 2012. 199(1): p. 9--13.
[5]
Mounkes, L., et al., The laminopathies: nuclear structure meets disease. Curr Opin Genet Dev, 2003. 13(3): p. 223--30.
[6]
Shumaker, D.K., et al., Mutant nuclear lamin A leads to progressive alterations of epigenetic control in premature aging. Proc Natl Acad Sci U S A, 2006. 103(23): p. 8703--8.
[7]
Goldman, R.D., et al., Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome. Proc Natl Acad Sci U S A, 2004. 101(24): p. 8963--8.
[8]
McCord, R.P., et al., Correlated alterations in genome organization, histone methylation, and DNA-lamin A/C interactions in Hutchinson-Gilford progeria syndrome. Genome Res, 2013. 23(2): p. 260--9.
[9]
Somech, R., et al., The nuclear-envelope protein and transcriptional repressor LAP2beta interacts with HDAC3 at the nuclear periphery, and induces histone H4 deacetylation. J Cell Sci, 2005. 118(Pt 17): p. 4017--25.
[10]
Gotzmann, J. and R. Foisner, A-type lamin complexes and regenerative potential: a step towards understanding laminopathic diseases? Histochem Cell Biol, 2006. 125(1-2): p. 33--41.
[11]
Wilson, K.L. and R. Foisner, Lamin-binding Proteins. Cold Spring Harb Perspect Biol, 2010. 2(4): p. a000554.
[12]
Park, W.Y., et al., Gene profile of replicative senescence is different from progeria or elderly donor. Biochem Biophys Res Commun, 2001. 282(4): p. 934--9.
[13]
Ly, D.H., et al., Mitotic misregulation and human aging. Science, 2000. 287(5462): p. 2486--92.
[14]
Csoka, A.B., et al., Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging Cell, 2004. 3(4): p. 235--43.
[15]
Marji, J., et al., Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition. PLoS One, 2010. 5(6): p. e11132.
[16]
Stranger, B.E., et al., Population genomics of human gene expression. Nat Genet, 2007. 39(10): p. 1217--24.
[17]
Trapnell, C., et al., Differential gene and transcript expression analysis of RNA-seq experiments with TopHat and Cufflinks. Nat Protoc, 2012. 7(3): p. 562--78.
[18]
Barrett, T., et al., NCBI GEO: archive for functional genomics data sets--10 years on. Nucleic Acids Res, 2011. 39(Database issue): p. D1005--10.
[19]
Myatt, S.S. and E.W. Lam, The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer, 2007. 7(11): p. 847--59.
Index Terms
- Identification of gene clusters with phenotype-dependent expression with application to normal and premature ageing
Recommendations
Phenotype-dependent coexpression gene clusters: application to normal and premature ageing
Hutchinson Gilford progeria syndrome (HGPS) is a rare genetic disease with symptoms of aging at a very early age. Its molecular basis is not entirely clear, although profound gene expression changes have been reported, and there are some known and other ...
Meta-analysis of age-related gene expression profiles identifies common signatures of aging
Motivation: Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and ...
Identifying time-lagged gene clusters using gene expression data
Motivation: Analysis of gene expression data can provide insights into the time-lagged co-regulation of genes/gene clusters. However, existing methods such as the Event Method and the Edge Detection Method are inefficient as they compare only two ...
Comments
Information & Contributors
Information
Published In
September 2013
987 pages
ISBN:9781450324342
DOI:10.1145/2506583
Copyright © 2013 ACM.
Permission to make digital or hard copies of all or part of this work for personal or classroom use is granted without fee provided that copies are not made or distributed for profit or commercial advantage and that copies bear this notice and the full citation on the first page. Copyrights for components of this work owned by others than ACM must be honored. Abstracting with credit is permitted. To copy otherwise, or republish, to post on servers or to redistribute to lists, requires prior specific permission and/or a fee. Request permissions from [email protected]
Sponsors
Publisher
Association for Computing Machinery
New York, NY, United States
Publication History
Published: 22 September 2013
Check for updates
Author Tags
Qualifiers
- Tutorial
- Research
- Refereed limited
Conference
BCB'13
Sponsor:
Acceptance Rates
BCB'13 Paper Acceptance Rate 43 of 148 submissions, 29%;
Overall Acceptance Rate 254 of 885 submissions, 29%
Upcoming Conference
Contributors
Other Metrics
Bibliometrics & Citations
Bibliometrics
Article Metrics
- 0Total Citations
- 118Total Downloads
- Downloads (Last 12 months)2
- Downloads (Last 6 weeks)1
Reflects downloads up to 22 Sep 2024
Other Metrics
Citations
View Options
Get Access
Login options
Check if you have access through your login credentials or your institution to get full access on this article.
Sign in