The GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and p... more The GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte–monocyte progenitor differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in mast cell differentiation and maintenance have not been delineated. We identified GATA2 is essential for pre-basophil and mast cell progenitors (pre-BMPs) to differentiate into mast cells. We found that GATA2 is critical in maintaining the expression of a wide range of genes that are important for performing mast cell functions. To determine the in vivo role of GATA2 in mast cell development, we generated connective tissue mast cell-specific Gata2 deficient mice. We found that Gata2 was required for connective tissue mast cell development. These mice failed to develop IgE-mediated anaphylaxis. GATA2 regulated the expression of Hdc gene, which is critical for IgE-mediated anaphylaxis, by binding to regulatory regions of the Hdc gene to promote its t...
Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against ... more Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against pre-leukemic clonal expansion. Acute exposure to the pro-inflammatory cytokine interleukin (IL)-1 drives myeloid cell production and HSC cell cycle entry. However, HSC return to a quiescent state suggesting the presence of a ‘braking’ mechanism that limits HSC proliferative capacity during chronic inflammation. To identify mechanism(s) regulating HSC cell cycle activity, we injected mice with IL-1 for 20 days modeling chronic inflammation in vivo. RNA-seq analysis of HSC following IL-1 exposure revealed repression of cell cycle and protein synthesis genes, suggesting the activation of a ‘growth arrest’ gene program. This gene program coincided with increased PU.1 expression, and ChIP-seq analysis identified PU.1 binding on nearly all repressed genes, suggesting PU.1 enforces HSC quiescence during chronic inflammation. Strikingly, HSC from IL-1 treated PU.1-deficient mice exhibited loss o...
1Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Harvard Medical Scho... more 1Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR 72205, USA 3Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Beijing Advanced Innovation Center for Human Brain Protection, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China 4Adobe Inc., San Jose, CA 95110, USA 5Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China 6Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA 71 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China 8National Research Center for Translational Medicine, Shanghai State Ke...
Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that ... more Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo. Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyte-independent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via ...
We have reported that JMJD5 and JMJD7 (JMJD5/7) are responsible for the clipping of arginine meth... more We have reported that JMJD5 and JMJD7 (JMJD5/7) are responsible for the clipping of arginine methylated histone tails to generate "tailless nucleosomes", which could release the pausing RNA polymerase II (Pol II) into productive transcription elongation. JMJD5/7 function as endopeptidases that cleave histone tails specifically adjacent to methylated arginine residues and continue to degrade N-terminal residues of histones via their aminopeptidase activity. Here, we report structural and biochemical studies on JMJD5/7 to understand the basis of substrate recognition and catalysis mechanism by this JmjC subfamily. Recognition between these enzymes and histone substrates is specific, which is reflected by the binding data between enzymes and substrates. High structural similarity between JMJD5 and JMJD7 is reflected by the shared common substrates and high binding affinity. However, JMJD5 does not bind to arginine methylated histone tails with additional lysine acetylation wh...
Proceedings of the National Academy of Sciences, 2010
Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated ... more Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a ( mb-1 ) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of “committed” pro-B cells were maintained in Ebf1 +/− Runx1 +/− ( ER het ) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, κ 0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER het pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER het mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1 +/− ( E het ) mice and were nearly absent in ER het mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Ig κ rearrangements, a relative lack of Ig λ rearrangements was detected in E h...
this report, we show that mb-1 transcription correlates with occupancy of multiple promoter bindi... more this report, we show that mb-1 transcription correlates with occupancy of multiple promoter binding sites by factors in vivo. Using in vivo footprinting, we identified at least six factor binding sites and showed their importance for transcription in early B cells. Each of the sequences protected from DMS modification in intact cells contributed to promoter function in a cell type-specific manner, as evidenced by decreased activity of mutated promoters in short-term transfection assays. These data are supported by Western and EMSA analysis of proteins in representative cell lines, which showed that levels of EBF and Pax-5 proteins in cells correlate with protection of their binding sites in footprinting assays and requirements for these sites in mb-1 promoter function. DNA microarray experiments identified a very close correlation between mb-1 and EBF expression. Thus, the data suggest that mb-1 promoter function is most directly regulated by levels of EBF, but all three factors are...
B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by tran... more B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by transcription factors. One of the most important regulators of this process is Early B cell Factor (EBF). Multiple lines of evidence indicate that expression of EBF is a principle determinant of the B cell fate. In the absence of EBF, progenitor cells fail to express classical markers of B cells, including immunoglobulins. EBF drives B cell differentiation by activating the Pax5 gene and other genes required for the pre-B and B cell receptors. New evidence suggests that expression of EBF in common lymphoid progenitors directs B cell fate decisions. Specification and commitment of cells to the B cell lineage are further established by Pax5, which increases expression of EBF. Recently, it was demonstrated that both EBF and Pax5 contribute to the commitment of cells to the B lineage. Together, these studies confirm that EBF is a keystone in a regulatory network that coordinates B cell lineage s...
One of the central proteins in B-lymphocyte development is the transcription factor early B-cell ... more One of the central proteins in B-lymphocyte development is the transcription factor early B-cell factor 1 (Ebf1). Ebf1 is critical for the activation of B-lineage restricted genes in the earliest B-lineage progenitors and for restriction of lineage fate options. The activity is highly dependent on functional Ebf1 dose because mice carrying a heterozygous deletion of the Ebf1 gene display reduced numbers of CD19CD43 B-cell progenitors, whereas the CD19CD43 proB cell compartment remains intact. Ebf1 levels are also of relevance in leukemia because mutations resulting in reduced functional EBF1 dose and increased expression of post-transcriptional inhibitors of EBF1, ZNF521, or ZNF423 are found in B-cell acute lymphoblastic leukemia (B-ALL).Adirect role forEbf1dose inmalignant transformation was supported by the findings that combined expression of constitutively active Stat5 (caStat5) and heterozygous loss of eitherEbf1 or Pax5 results in B-cell leukemia inmice. Heterozygote deletion ...
Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, ... more Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated genes ( ) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes BM microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521's role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
Cell lineage specification is a tightly regulated process that is dependent on appropriate expres... more Cell lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage and developmental stage-specific transcriptional programs. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in B cell progenitors in vivo, development of these cells is arrested at an early pro-B-like stage that is unresponsive to IL-7 receptor signaling and unable to efficiently complete V(D)J rearrangements at Igh loci. Our studies confirm that chromatin accessibility and transcription of thousands of gene loci are controlled dynamically by CHD4 during early B cell development. Strikingly, CHD4-deficient pro-B cells express transcripts of many non-B cell lineage genes, including genes that are characteristic of other hematopoietic lineages...
Hematopoietic stem cell (HSC) quiescence is crucial for maintaining lifelong blood production and... more Hematopoietic stem cell (HSC) quiescence is crucial for maintaining lifelong blood production and preventing potentially toxic overproduction of blood cells. HSC are capable of re-entering quiescence following exposure to pro-inflammatory stimuli such as interleukin (IL)-1, implying the existence of one or more 'braking' mechanisms that limit and/or overcome the mitogenic properties of these signals to limit HSC cell cycle entry. However, mechanism(s) regulating HSC quiescence during chronic inflammation have yet to be fully elucidated. In the present study, we find that the master myeloid transcription factor PU.1 represses Myc-regulated cell cycle and protein synthesis pathways in HSC during chronic inflammation, thereby guarding HSC quiescence in this context. To gain insight into HSC cell cycle regulation in the context of chronic inflammatory signaling, we performed cell cycle and RNA-seq analysis on purified HSC from mice injected daily for 20 days with IL-1β. Striking...
The Journal of allergy and clinical immunology, Jan 24, 2017
Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized ... more Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the histidine decarboxylase (Hdc) gene-encoded enzyme HDC. However, regulation of the Hdc gene in mast cells is poorly understood. We sought to investigate the in vivo regulation of IgE/mast cell-mediated anaphylaxis by the transcription factors GATA2 and microphthalmia-associated transcription factor (MITF) and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells. Mice deficient in the transcription factors Gata2, aryl hydrocarbon receptor (Ahr), aryl hydrocarbon receptor repressor (Ahrr), or basic helix-loop-helix family member E40 (Bhlhe40) were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. ...
The GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and p... more The GATA binding protein 2 (GATA2) plays critical roles in hematopoietic stem cell survival and proliferation, granulocyte–monocyte progenitor differentiation, and basophil and mast cell differentiation. However, precise roles of GATA2 in mast cell differentiation and maintenance have not been delineated. We identified GATA2 is essential for pre-basophil and mast cell progenitors (pre-BMPs) to differentiate into mast cells. We found that GATA2 is critical in maintaining the expression of a wide range of genes that are important for performing mast cell functions. To determine the in vivo role of GATA2 in mast cell development, we generated connective tissue mast cell-specific Gata2 deficient mice. We found that Gata2 was required for connective tissue mast cell development. These mice failed to develop IgE-mediated anaphylaxis. GATA2 regulated the expression of Hdc gene, which is critical for IgE-mediated anaphylaxis, by binding to regulatory regions of the Hdc gene to promote its t...
Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against ... more Hematopoietic stem cell (HSC) quiescence supports lifelong blood regeneration and guards against pre-leukemic clonal expansion. Acute exposure to the pro-inflammatory cytokine interleukin (IL)-1 drives myeloid cell production and HSC cell cycle entry. However, HSC return to a quiescent state suggesting the presence of a ‘braking’ mechanism that limits HSC proliferative capacity during chronic inflammation. To identify mechanism(s) regulating HSC cell cycle activity, we injected mice with IL-1 for 20 days modeling chronic inflammation in vivo. RNA-seq analysis of HSC following IL-1 exposure revealed repression of cell cycle and protein synthesis genes, suggesting the activation of a ‘growth arrest’ gene program. This gene program coincided with increased PU.1 expression, and ChIP-seq analysis identified PU.1 binding on nearly all repressed genes, suggesting PU.1 enforces HSC quiescence during chronic inflammation. Strikingly, HSC from IL-1 treated PU.1-deficient mice exhibited loss o...
1Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Harvard Medical Scho... more 1Department of Cancer Immunology and Virology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Science, Little Rock, AR 72205, USA 3Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Beijing Advanced Innovation Center for Human Brain Protection, School of Pharmaceutical Sciences, Tsinghua University, Beijing 100084, China 4Adobe Inc., San Jose, CA 95110, USA 5Department of Dermatology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China 6Department of Biomedical Research, National Jewish Health, Denver, CO 80206, USA 71 Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China 8National Research Center for Translational Medicine, Shanghai State Ke...
Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that ... more Alternative splicing (AS) of pre-mRNA is a critical component of transcriptional regulation that diversifies the cellular proteome. The Serine-Arginine Protein Kinases (SRPK) initiate early events in AS. Using conditional knockout mice (cKO), we demonstrated the importance of the X-linked gene Srpk3 in B lymphocyte development and in response to immunization in vivo. Significantly decreased numbers of immature and mature B cells were observed in Srpk3-cKO BM relative to wild-type (WT). Immunization of Srpk3-cKO mice with a T lymphocyte-independent type-2 antigen elicited greatly reduced amounts of specific IgG3. Srpk3 deletion resulted in hundreds of differentially spliced mRNAs in B cells, including mRNAs encoding proteins associated with signaling pathways and mitochondrial function. Several alternative splicing outcomes in Srpk3-cKO cells are due to altered splicing regulation of SR proteins. We conclude that Srpk3 is an immunomodulatory kinase that controls humoral immunity via ...
We have reported that JMJD5 and JMJD7 (JMJD5/7) are responsible for the clipping of arginine meth... more We have reported that JMJD5 and JMJD7 (JMJD5/7) are responsible for the clipping of arginine methylated histone tails to generate "tailless nucleosomes", which could release the pausing RNA polymerase II (Pol II) into productive transcription elongation. JMJD5/7 function as endopeptidases that cleave histone tails specifically adjacent to methylated arginine residues and continue to degrade N-terminal residues of histones via their aminopeptidase activity. Here, we report structural and biochemical studies on JMJD5/7 to understand the basis of substrate recognition and catalysis mechanism by this JmjC subfamily. Recognition between these enzymes and histone substrates is specific, which is reflected by the binding data between enzymes and substrates. High structural similarity between JMJD5 and JMJD7 is reflected by the shared common substrates and high binding affinity. However, JMJD5 does not bind to arginine methylated histone tails with additional lysine acetylation wh...
Proceedings of the National Academy of Sciences, 2010
Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated ... more Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a ( mb-1 ) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of “committed” pro-B cells were maintained in Ebf1 +/− Runx1 +/− ( ER het ) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, κ 0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER het pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER het mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1 +/− ( E het ) mice and were nearly absent in ER het mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Ig κ rearrangements, a relative lack of Ig λ rearrangements was detected in E h...
this report, we show that mb-1 transcription correlates with occupancy of multiple promoter bindi... more this report, we show that mb-1 transcription correlates with occupancy of multiple promoter binding sites by factors in vivo. Using in vivo footprinting, we identified at least six factor binding sites and showed their importance for transcription in early B cells. Each of the sequences protected from DMS modification in intact cells contributed to promoter function in a cell type-specific manner, as evidenced by decreased activity of mutated promoters in short-term transfection assays. These data are supported by Western and EMSA analysis of proteins in representative cell lines, which showed that levels of EBF and Pax-5 proteins in cells correlate with protection of their binding sites in footprinting assays and requirements for these sites in mb-1 promoter function. DNA microarray experiments identified a very close correlation between mb-1 and EBF expression. Thus, the data suggest that mb-1 promoter function is most directly regulated by levels of EBF, but all three factors are...
B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by tran... more B lymphocytes are generated from hematopoietic stem cells in a series of steps controlled by transcription factors. One of the most important regulators of this process is Early B cell Factor (EBF). Multiple lines of evidence indicate that expression of EBF is a principle determinant of the B cell fate. In the absence of EBF, progenitor cells fail to express classical markers of B cells, including immunoglobulins. EBF drives B cell differentiation by activating the Pax5 gene and other genes required for the pre-B and B cell receptors. New evidence suggests that expression of EBF in common lymphoid progenitors directs B cell fate decisions. Specification and commitment of cells to the B cell lineage are further established by Pax5, which increases expression of EBF. Recently, it was demonstrated that both EBF and Pax5 contribute to the commitment of cells to the B lineage. Together, these studies confirm that EBF is a keystone in a regulatory network that coordinates B cell lineage s...
One of the central proteins in B-lymphocyte development is the transcription factor early B-cell ... more One of the central proteins in B-lymphocyte development is the transcription factor early B-cell factor 1 (Ebf1). Ebf1 is critical for the activation of B-lineage restricted genes in the earliest B-lineage progenitors and for restriction of lineage fate options. The activity is highly dependent on functional Ebf1 dose because mice carrying a heterozygous deletion of the Ebf1 gene display reduced numbers of CD19CD43 B-cell progenitors, whereas the CD19CD43 proB cell compartment remains intact. Ebf1 levels are also of relevance in leukemia because mutations resulting in reduced functional EBF1 dose and increased expression of post-transcriptional inhibitors of EBF1, ZNF521, or ZNF423 are found in B-cell acute lymphoblastic leukemia (B-ALL).Adirect role forEbf1dose inmalignant transformation was supported by the findings that combined expression of constitutively active Stat5 (caStat5) and heterozygous loss of eitherEbf1 or Pax5 results in B-cell leukemia inmice. Heterozygote deletion ...
Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, ... more Zinc finger protein 521 (ZFP521), a DNA-binding protein containing 30 Krüppel-like zinc fingers, has been implicated in the differentiation of multiple cell types, including hematopoietic stem and progenitor cells (HSPC) and B lymphocytes. Here, we report a novel role for ZFP521 in regulating the earliest stages of hematopoiesis and lymphoid cell development via a cell-extrinsic mechanism. Mice with inactivated genes ( ) possess reduced frequencies and numbers of hematopoietic stem and progenitor cells, common lymphoid progenitors, and B and T cell precursors. Notably, ZFP521 deficiency changes BM microenvironment cytokine levels and gene expression within resident HSPC, consistent with a skewing of hematopoiesis away from lymphopoiesis. These results advance our understanding of ZFP521's role in normal hematopoiesis, justifying further research to assess its potential as a target for cancer therapies.
Cell lineage specification is a tightly regulated process that is dependent on appropriate expres... more Cell lineage specification is a tightly regulated process that is dependent on appropriate expression of lineage and developmental stage-specific transcriptional programs. Here, we show that Chromodomain Helicase DNA-binding protein 4 (CHD4), a major ATPase/helicase subunit of Nucleosome Remodeling and Deacetylase Complexes (NuRD) in lymphocytes, is essential for specification of the early B cell lineage transcriptional program. In the absence of CHD4 in B cell progenitors in vivo, development of these cells is arrested at an early pro-B-like stage that is unresponsive to IL-7 receptor signaling and unable to efficiently complete V(D)J rearrangements at Igh loci. Our studies confirm that chromatin accessibility and transcription of thousands of gene loci are controlled dynamically by CHD4 during early B cell development. Strikingly, CHD4-deficient pro-B cells express transcripts of many non-B cell lineage genes, including genes that are characteristic of other hematopoietic lineages...
Hematopoietic stem cell (HSC) quiescence is crucial for maintaining lifelong blood production and... more Hematopoietic stem cell (HSC) quiescence is crucial for maintaining lifelong blood production and preventing potentially toxic overproduction of blood cells. HSC are capable of re-entering quiescence following exposure to pro-inflammatory stimuli such as interleukin (IL)-1, implying the existence of one or more 'braking' mechanisms that limit and/or overcome the mitogenic properties of these signals to limit HSC cell cycle entry. However, mechanism(s) regulating HSC quiescence during chronic inflammation have yet to be fully elucidated. In the present study, we find that the master myeloid transcription factor PU.1 represses Myc-regulated cell cycle and protein synthesis pathways in HSC during chronic inflammation, thereby guarding HSC quiescence in this context. To gain insight into HSC cell cycle regulation in the context of chronic inflammatory signaling, we performed cell cycle and RNA-seq analysis on purified HSC from mice injected daily for 20 days with IL-1β. Striking...
The Journal of allergy and clinical immunology, Jan 24, 2017
Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized ... more Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the histidine decarboxylase (Hdc) gene-encoded enzyme HDC. However, regulation of the Hdc gene in mast cells is poorly understood. We sought to investigate the in vivo regulation of IgE/mast cell-mediated anaphylaxis by the transcription factors GATA2 and microphthalmia-associated transcription factor (MITF) and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells. Mice deficient in the transcription factors Gata2, aryl hydrocarbon receptor (Ahr), aryl hydrocarbon receptor repressor (Ahrr), or basic helix-loop-helix family member E40 (Bhlhe40) were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. ...
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Papers by James Hagman