James Douglas Engel

Concordia University–Ann Arbor, Ann Arbor, Michigan, United States

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Publications (102)651.83 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Functional relationship networks, which summarize the probability of co-functionality between any two genes in the genome, could complement the reductionist focus of modern biology for understanding diverse biological processes in an organism. One major limitation of the current networks is that they are static while one might expect functional relationships to consistently reprogram during the differentiation of a cell lineage. To address this potential limitation, we developed a novel algorithm that leverages both differentiation stage-specific expression data and large-scale, heterogeneous functional genomic data to model such dynamic changes. We then applied this algorithm to the time-course RNA-Seq data we collected for ex vivo human erythroid cell differentiation.
    Bioinformatics (Oxford, England). 08/2014;
  • Mikiko Suzuki, Masayuki Yamamoto, James Douglas Engel
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    ABSTRACT: The human β-globin locus is comprised of embryonic, fetal and adult globin genes that are expressed in a developmental stage-specific manner. Mutations in the globin locus give rise to the β-globinopathies, β-thalassemia and sickle cell disease, that begin to manifest symptoms around the time of birth. Although the fetal globin genes are autonomously silenced in adult stage erythroid cells, mutations lying both within and outside of the locus lead to natural variations in the level of fetal globin gene expression, and some of these significantly ameliorate the clinical symptoms of the β-globinopathies. Multiple reports have now identified several transcription factors that are involved in fetal globin gene repression in definitive (adult) stage erythroid cells (the TR2/TR4 heterodimer, c-Myb, KLFs, BCL11A, and SOX6). To carry out their repression functions, chromatin modifying enzymes (such as DNA methyltransferase, histone deacetylases and lysine-specific histone demethylase 1) are additionally involved as a consequence of forming large macromolecular complexes with the DNA-binding subunits of these cellular machines. This review focuses on the molecular mechanisms underlying fetal globin gene silencing and possible near future molecularly-targeted therapies for treating the β-globinopathies.
    Molecular and cellular biology. 07/2014;
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    ABSTRACT: We previously reported that TR2 and TR4 orphan nuclear receptors bind to direct repeat (DR) elements in the ε- and γ-globin promoters, and act as molecular anchors for the recruitment of epigenetic corepressors of the multifaceted DRED complex, thereby leading to ε- and γ-globin transcriptional repression during definitive erythropoiesis. Other than the ε- and γ-globin and the GATA1 genes, TR4-regulated target genes in human erythroid cells remain unknown. Here, we identified TR4 binding sites genome-wide using chromatin immunoprecipitation followed by massively parallel sequencing (ChIP-seq) as human primary CD34+ hematopoietic progenitors differentiated progressively to late erythroid precursors. We also performed whole transcriptome analyses by RNA-seq to identify TR4 downstream targets after lentiviral-mediated TR4 shRNA knockdown in erythroid cells. Analyses from combined ChIP-seq and RNA-seq datasets indicate that DR1 motifs are more prevalent in the proximal promoters of TR4 direct target genes, which are involved in basic biological functions (e.g., mRNA processing, ribosomal assembly, RNA splicing and primary metabolic processes). In contrast, other non-DR1 repeat motifs (DR4, ER6 and IR1) are more prevalent at gene-distal TR4 binding sites. Of these, approximately 50% are also marked with epigenetic chromatin signatures (such as P300, H3K27ac, H3K4me1 and H3K27me3) associated with enhancer function. Thus, we hypothesize that TR4 regulates gene transcription via gene-proximal DR1 sites as TR4/TR2 heterodimers, while it can associate with novel nuclear receptor partners (such as RXR) to bind to distant non-DR1 consensus sites. In summary, this study reveals that the TR4 regulatory network is far more complex than previously appreciated and that TR4 regulates basic, essential biological processes during the terminal differentiation of human erythroid cells.
    PLoS Genetics 05/2014; 10(5):e1004339. · 8.52 Impact Factor
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    ABSTRACT: To globally survey the changes in transcriptional landscape during terminal erythroid differentiation, we performed RNA sequencing (RNA-seq) on primary human CD34(+) cells after ex vivo differentiation from the earliest into the most mature erythroid cell stages. This analysis identified thousands of novel intergenic and intronic transcripts as well as novel alternative transcript isoforms. After rigorous data filtering, 51 (presumptive) novel protein-coding transcripts, 5,326 long and 679 small non-coding RNA candidates remained. The analysis also revealed two clear transcriptional trends during terminal erythroid differentiation: first, that the complexity of transcript diversity was predominantly achieved by alternative splicing, and second, that splicing junctional diversity diminished during erythroid differentiation. Finally, 404 genes that were not known previously to be differentially expressed in erythroid cells were annotated. Analysis of the most extremely differentially expressed transcripts revealed that these gene products were all closely associated with hematopoietic lineage differentiation. Taken together, this study will serve as a comprehensive platform for future in-depth investigation of human erythroid development that, in turn, may reveal new insights into multiple layers of the transcriptional regulatory hierarchy that controls erythropoiesis.
    Human Molecular Genetics 04/2014; · 7.69 Impact Factor
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    ABSTRACT: Chromosomal inversion between 3q21 and 3q26 results in high-risk acute myeloid leukemia (AML). In this study, we identified a mechanism whereby a GATA2 distal hematopoietic enhancer (G2DHE or -77-kb enhancer) is brought into close proximity to the EVI1 gene in inv(3)(q21;q26) inversions, leading to leukemogenesis. We examined the contribution of G2DHE to leukemogenesis by creating a bacterial artificial chromosome (BAC) transgenic model that recapitulates the inv(3)(q21;q26) allele. Transgenic mice harboring a linked BAC developed leukemia accompanied by EVI1 overexpression-neoplasia that was not detected in mice bearing the same transgene but that was missing the GATA2 enhancer. These results establish the mechanistic basis underlying the pathogenesis of a severe form of leukemia through aberrant expression of the EVI1 proto-oncogene.
    Cancer cell 04/2014; · 25.29 Impact Factor
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    ABSTRACT: PPARγ coactivator-1 (PGC-1) α and β have been shown to be intimately involved in the transcriptional regulation of cellular energy metabolism as well as other biological processes, but both coactivator proteins are expressed in many other tissues and organs in which their function is, in essence, unexplored. Here, we found that PGC-1 proteins are both abundantly expressed in maturing erythroid cells. PGC-1α and -1β compound null mutant (Pgc-1(c)) animals express less β-like globin mRNAs throughout development, and consequently neonatal Pgc-1(c) mice exhibited growth retardation and profound anemia. Flow cytometry shows that the number of mature erythrocytes is markedly reduced in neonatal Pgc-1(c) pups, indicating that erythropoiesis is severely compromised. Furthermore, hematoxylin and eosin staining revealed necrotic cell death and cell loss in Pgc-1(c) livers and spleen. Chromatin immunoprecipitation studies revealed that both PGC-1α and -1β as well as two nuclear receptors, TR2 and TR4, coordinately bind to the various globin gene promoters. In addition, PGC-1α and -1β can interact with TR4 to potentiate transcriptional activation. These data provide new insights into our understanding of globin gene regulation and raise the interesting possibility that the PGC-1 coactivators can interact with TR4 to elicit differential stage-specific effects on globin gene transcription.
    Molecular and cellular biology 03/2014; · 6.06 Impact Factor
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    ABSTRACT: The transcription factor GATA2 plays pivotal roles in early renal development, but its distribution and physiological functions in adult kidney is largely unknown. We examined the GATA2 expression pattern in the adult kidney by tracing GFP fluorescence in Gata2(GFP/+) mice that recapitulate endogenous GATA2 expression and found a robust GFP expression specifically in the renal medulla. Upon purification of the GFP-positive cells, we found that collecting duct (CD)-specific markers including Aquaporin 2 (Aqp2), an important channel for water reabsorption from urine, were abundantly expressed. To address the physiological function of GATA2 in the CD cells, we generated renal tubular cell-specific Gata2-deficient mice (Gata2-CKO) by crossing Gata2 floxed mice with inducible Pax8-Cre mice. We found that the Gata2-CKO mice showed a significant decrease in Aqp2 expression. The Gata2-CKO mice exhibited high 24-hr urine volume and low urine osmolality, two important signs of diabetes insipidus. We introduced biotin-tagged GATA2 into a mouse CD-derived cell line and conducted chromatin pull-down assays, which revealed direct GATA2-binding to conserved GATA motifs in the Aqp2 promoter region. A luciferase reporter assay using an Aqp2 promoter-reporter showed that GATA2 trans-activates Aqp2 through the GATA motifs. These results demonstrate that GATA2 regulates the Aqp2 gene expression in CD cells and contributes to the maintenance of the body-water homeostasis.
    Molecular and cellular biology 03/2014; · 6.06 Impact Factor
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    ABSTRACT: Infantile hypertrophic pyloric stenosis (IHPS) is a common birth anomaly characterized by obstruction of the pyloric lumen. A genome-wide association study implicated NKX2-5, which encodes a transcription factor that is expressed in embryonic heart and pylorus, in the pathogenesis of IHPS. However, the function of the NKX2-5 in pyloric smooth muscle development has not been directly examined. We investigated the pattern of Nkx2-5 during the course of murine pyloric sphincter development and examined co-expression of Nkx2-5 with Gata3 and Sox9-other transcription factors with pyloric-specific mesenchymal expression. We also assessed pyloric sphincter development in mice with disruption of Nkx2-5 or Gata3. We used immunofluorescence analysis to compare levels of NKX2-5, GATA3, and SOX9 in different regions of smooth muscle cells. Pyloric development was assessed in mice with conditional or germline deletion of Nkx2-5 or Gata3, respectively. Gata3, Nkx2-5, and Sox9 were co-expressed in differentiating smooth muscle cells of a distinct fascicle of the pyloric outer longitudinal muscle (OLM). Expansion of this fascicle coincided with development of the pyloric sphincter. Disruption of Nkx2-5 or Gata3 caused severe hypoplasia of this fascicle and alters pyloric muscle shape. Although expression of Sox9 required Nkx2-5 and Gata3, there was no apparent hierarchical relationship between Nkx2-5 and Gata3 during pyloric OLM development. Nkx2-5 and Gata3 are independently required for the development of a pyloric OLM fascicle, which required for pyloric sphincter morphogenesis, in mice. These data indicate that regulatory changes that alter Nkx2-5 or Gata3 expression could contribute to pathogenesis of IHPS.
    Gastroenterology 10/2013; · 12.82 Impact Factor
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    ABSTRACT: In previous mass spectrometry and co-immune precipitation studies, we identified TRIM28 (TIF-1β, KAP-1) as a cofactor that specifically co-purified with an NR2C1/NR2C2 (TR2/TR4) orphan nuclear receptor heterodimer that previous studies had implicated as an embryonic/fetal β-type globin gene repressor. TRIM28 has been characterized as a transcriptional co-repressor that can associate with many different transcription factors and can play functional roles in multiple tissues and cell types. Here we tested the contribution of TRIM28 to globin gene regulation and erythropoiesis using a conditional loss of function in vivo model. We discovered that Trim28 genetic loss in the adult mouse leads to defective immature erythropoiesis in the bone marrow and consequently to anemia. We further found that TRIM28 controls erythropoiesis in a cell-autonomous manner by inducibly deleting Trim28 exclusively in hematopoietic cells. Finally, in the absence of TRIM28 we observed increased apoptosis as well as diminished expression of multiple erythroid transcription factors and heme biosynthetic enzymes in immature erythroid cells. Thus, TRIM28 is essential for the cell-autonomous development of immature erythroblasts in the bone marrow.
    Blood 10/2013; · 9.78 Impact Factor
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    ABSTRACT: The human β-globin locus is comprised of embryonic, fetal and adult globin genes, each of which is expressed at distinct stages of pre- and post-natal development. Functional defects in globin proteins or expression results in mild to severe anemia, such as in sickle-cell disease or β-thalassemia, but the clinical symptoms of both disorders are ameliorated by persistent expression of the fetal globin genes. Recent genome wide association studies (GWAS) identified the intergenic region between the HBS1L and MYB loci as a candidate modifier of fetal hemoglobin expression in adults. However, it remains to be clarified whether the enhancer activity within the HBS1L-MYB regulatory domain contributes to the production of fetal hemoglobin in adults. Here we report a new mouse model of hereditary persistence of fetal hemoglobin (HPFH) in which a transgene randomly inserted into the orthologous murine Hbs1l-Myb locus. This mutant mouse exhibited typically elevated expression of embryonic globins and hematopoietic parameters similar to those observed in human HPFH. These results support the contention that mutation of the HBS1L-MYB genomic domain is responsible for elevated expression of the fetal globin genes, and this model serves as an important means in the analysis of networks that regulate fetal globin gene expression.
    Molecular and cellular biology 02/2013; · 6.06 Impact Factor
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    ABSTRACT: Enhanced fetal γ-globin synthesis alleviates symptoms of β-globinopathies such as sickle cell disease and β-thalassemia, but current γ-globin-inducing drugs offer limited beneficial effects. We show here that lysine-specific demethylase 1 (LSD1) inhibition by RNAi in human erythroid cells or by the monoamine oxidase inhibitor tranylcypromine in human erythroid cells or β-type globin-transgenic mice enhances γ-globin expression. LSD1 is thus a promising therapeutic target for γ-globin induction, and tranylcypromine may serve as a lead compound for the development of a new γ-globin inducer.
    Nature medicine 02/2013; 19(3):291-4. · 27.14 Impact Factor
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    ABSTRACT: The transcription factor GATA-2 plays vital roles in quite diverse developmental programs, including hematopoietic stem cell (HSC) survival and proliferation. We previously identified a vascular endothelial (VE) enhancer that regulates GATA-2 activity in pan-endothelial cells. To more thoroughly define the in vivo regulatory properties of this enhancer, we generated a tamoxifen-inducible Cre transgenic mouse line using the Gata2 VE enhancer (Gata2 VECre) and utilized it to temporally direct tissue-specific conditional loss of Gata2. Here, we report that Gata2 VECre-mediated loss of GATA-2 led to anemia, hemorrhage, and eventual death in edematous embryos. We further determined that the etiology of anemia in conditional Gata2 mutant embryos involved HSC loss in the fetal liver, as demonstrated by in vitro colony-forming and immunophenotypic as well as in vivo long-term competitive repopulation experiments. We further documented that the edema and hemorrhage in conditional Gata2 mutant embryos were due to defective lymphatic development. Thus, we unexpectedly discovered that in addition to its contribution to endothelial cell development, the VE enhancer also regulates GATA-2 expression in definitive fetal liver and adult BM HSCs, and that GATA-2 function is required for proper lymphatic vascular development during embryogenesis.
    The Journal of clinical investigation 09/2012; 122(10):3705-17. · 15.39 Impact Factor
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    ABSTRACT: NF-E2-related factor 2 (Nrf2) is a key transcription factor that is critical for cellular defense against oxidative and xenobiotic insults. Nrf2 heterodimerizes with small Maf (sMaf) proteins and binds to antioxidant response elements (AREs) to activate a battery of cytoprotective genes. However, it remains unclear to what extent the Nrf2-sMaf heterodimers contribute to ARE-dependent gene regulation on a genome-wide scale. We performed chromatin immunoprecipitation coupled with high-throughput sequencing and identified the binding sites of Nrf2 and MafG throughout the genome. Compared to sites occupied by Nrf2 alone, many sites co-occupied by Nrf2 and MafG exhibit high enrichment and are located in species-conserved genomic regions. The ARE motifs were significantly enriched among the recovered Nrf2-MafG-binding sites but not among the Nrf2-binding sites that did not display MafG binding. The majority of the Nrf2-regulated cytoprotective genes were found in the vicinity of Nrf2-MafG-binding sites. Additionally, sequences that regulate glucose metabolism and several amino acid transporters were identified as Nrf2-MafG target genes, suggesting diverse roles for the Nrf2-MafG heterodimer in stress response. These data clearly support the notion that Nrf2-sMaf heterodimers are complexes that regulate batteries of genes involved in various aspects of cytoprotective and metabolic functions through associated AREs.
    Nucleic Acids Research 09/2012; · 8.81 Impact Factor
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    ABSTRACT: During renal development, the proper emergence of the ureteric bud (UB) from the Wolffian duct is essential for formation of the urinary system. Previously, we showed that expression of transcription factor GATA-2 in the urogenital primordium was demarcated anteroposteriorly into two domains that were regulated by separate enhancers. While GATA-2 expression in the caudal urogenital mesenchyme is controlled by the UG4 enhancer, its more-rostral expression is regulated by UG2. We found that anteriorly displaced budding led to obstructed megaureters in Gata2 hypomorphic mutant mice, possibly due to reduced expression of the downstream effector bone morphogenetic protein 4 (BMP4). Here, we report that UG4-driven, but not UG2-driven, GATA-2 expression in the urogenital mesenchyme significantly reverts the uropathy observed in the Gata2 hypomorphic mutant mice. Furthermore, the data show that transgenic rescue by GATA-2 reverses the rostral outgrowth of the UB. We also provide evidence for a GATA-2-BMP4 epistatic relationship by demonstrating that reporter gene expression from a Bmp4 bacterial artificial chromosome (BAC) transgene is altered in Gata2 hypomorphs; furthermore, UG4-directed BMP4 expression in the mutants leads to reduced incidence of megaureters. These results demonstrate that GATA-2 expression in the caudal urogenital mesenchyme as directed by the UG4 enhancer is crucial for proper development of the urinary tract and that its regulation of BMP4 expression is a critical aspect of this function.
    Molecular and cellular biology 04/2012; 32(12):2312-22. · 6.06 Impact Factor
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    Chia-Jui Ku, Tomonori Hosoya, Ivan Maillard, James Douglas Engel
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    ABSTRACT: Maintaining hematopoietic stem cell (HSC) quiescence is a critical property for the life-long generation of blood cells. Approximately 75% of cells in a highly enriched long-term repopulating HSC (LT-HSC) pool (Lin(-)Sca1(+)c-Kit(hi)CD150(+)CD48(-)) are quiescent, with only a small percentage of the LT-HSCs in cycle. Transcription factor GATA-3 is known to be vital for the development of T cells at multiple stages in the thymus and for Th2 differentiation in the peripheral organs. Although it is well documented that GATA-3 is expressed in HSCs, a role for GATA-3 in any prethymic progenitor cell has not been established. In the present study, we show that Gata3-null mutant mice generate fewer LT-HSCs and that fewer Gata3-null LT-HSCs are in cycle. Furthermore, Gata3 mutant hematopoietic progenitor cells fail to be recruited into an increased cycling state after 5-fluorouracil-induced myelosuppression. Therefore, GATA-3 is required for the maintenance of a normal number of LT-HSCs and for their entry into the cell cycle.
    Blood 03/2012; 119(10):2242-51. · 9.78 Impact Factor
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    ABSTRACT: Embryogenesis is a period during which cells are exposed to dynamic changes of various intracellular and extracellular stresses. Oxidative stress response genes are regulated by heterodimers composed of Cap'n'Collar (CNC) and small Maf proteins (small Mafs) that bind to antioxidant response elements (ARE). Whereas CNC factors have been shown to contribute to the expression of ARE-dependent cytoprotective genes during embryogenesis, the specific contribution of small Maf proteins to such gene regulation remains to be fully examined. To delineate the small Maf function in vivo, in this study we examined mice lacking all three small Mafs (MafF, MafG, and MafK). The small Maf triple-knockout mice developed normally until embryonic day 9.5 (E9.5). Thereafter, however, the triple-knockout embryos showed severe growth retardation and liver hypoplasia, and the embryos died around E13.5. ARE-dependent cytoprotective genes were expressed normally in E10.5 triple-knockout embryos, but the expression was significantly reduced in the livers of E13.5 mutant embryos. Importantly, the embryonic lethality could be completely rescued by transgenic expression of exogenous MafG under MafG gene regulatory control. These results thus demonstrate that small Maf proteins are indispensable for embryonic development after E9.5, especially for liver development, but early embryonic development does not require small Mafs.
    Molecular and cellular biology 12/2011; 32(4):808-16. · 6.06 Impact Factor
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    ABSTRACT: Sickle cell disease (SCD) is a hematologic disorder caused by a missense mutation in the adult β-globin gene. Higher fetal hemoglobin (HbF) levels in red blood cells of SCD patients have been shown to improve morbidity and mortality. We previously found that nuclear receptors TR2 and TR4 repress expression of the human embryonic ε-globin and fetal γ-globin genes in definitive erythroid cells. Because forced expression of TR2/TR4 in murine adult erythroid cells paradoxically enhanced fetal γ-globin gene expression in transgenic mice, we wished to determine if forced TR2/TR4 expression in a SCD model mouse would result in elevated HbF synthesis and thereby alleviate the disease phenotype. In a "humanized" sickle cell model mouse, forced TR2/TR4 expression increased HbF abundance from 7.6% of total hemoglobin to 18.6%, accompanied by increased hematocrit from 23% to 34% and reticulocyte reduction from 61% to 18%, indicating a significant reduction in hemolysis. Moreover, forced TR2/TR4 expression reduced hepatosplenomegaly and liver parenchymal necrosis and inflammation in SCD mice, indicating alleviation of usual pathophysiological characteristics. This article shows that genetic manipulation of nonglobin proteins, or transcription factors regulating globin gene expression, can ameliorate the disease phenotype in a SCD model animal. This proof-of-concept study demonstrates that modulating TR2/TR4 activity in SCD patients may be a promising therapeutic approach to induce persistent HbF accumulation and for treatment of the disease.
    Proceedings of the National Academy of Sciences 11/2011; 108(46):18808-13. · 9.81 Impact Factor
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    ABSTRACT: Thalassaemia is one of the most common genetic diseases worldwide, with at least 60,000 severely affected individuals born every year. Individuals originating from tropical and subtropical regions are most at risk. Disorders of haemoglobin synthesis (thalassaemia) and structure (eg, sickle-cell disease) were among the first molecular diseases to be identified, and have been investigated and characterised in detail over the past 40 years. Nevertheless, treatment of thalassaemia is still largely dependent on supportive care with blood transfusion and iron chelation. Since 1978, scientists and clinicians in this specialty have met regularly in an international effort to improve the management of thalassaemia, with the aim of increasing the expression of unaffected fetal genes to improve the deficiency in adult β-globin synthesis. In this Seminar we discuss important advances in the understanding of the molecular and cellular basis of normal and abnormal expression of globin genes. We will summarise new approaches to the development of tailored pharmacological agents to alter regulation of globin genes, the first trial of gene therapy for thalassaemia, and future prospects of cell therapy.
    The Lancet 09/2011; 379(9813):373-83. · 39.21 Impact Factor
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    ABSTRACT: Nuclear receptors TR2 and TR4 (TR2/TR4) were previously shown to bind in vitro to direct repeat elements in the mouse and human embryonic and fetal β-type globin gene promoters and to play critical roles in the silencing of these genes. By chromatin immunoprecipitation (ChIP) we show that, in adult erythroid cells, TR2/TR4 bind to the embryonic β-type globin promoters but not to the adult β-globin promoter. We purified protein complexes containing biotin-tagged TR2/TR4 from adult erythroid cells and identified DNMT1, NuRD, and LSD1/CoREST repressor complexes, as well as HDAC3 and TIF1β, all known to confer epigenetic gene silencing, as potential corepressors of TR2/TR4. Coimmunoprecipitation assays of endogenous abundance proteins indicated that TR2/TR4 complexes consist of at least four distinct molecular species. In ChIP assays we found that, in undifferentiated murine adult erythroid cells, many of these corepressors associate with both the embryonic and the adult β-type globin promoters but, upon terminal differentiation, they specifically dissociate only from the adult β-globin promoter concomitant with its activation but remain bound to the silenced embryonic globin gene promoters. These data suggest that TR2/TR4 recruit an array of transcriptional corepressors to elicit adult stage-specific silencing of the embryonic β-type globin genes through coordinated epigenetic chromatin modifications.
    Molecular and cellular biology 06/2011; 31(16):3298-311. · 6.06 Impact Factor

Publication Stats

3k Citations
651.83 Total Impact Points

Institutions

  • 2003–2014
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2011
    • Tohoku University
      • Department of Medical Biochemistry
      Sendai, Kagoshima, Japan
  • 2004–2011
    • University of Michigan
      • • Department of Cell and Developmental Biology
      • • Department of Electrical Engineering and Computer Science (EECS)
      Ann Arbor, MI, United States
  • 2009
    • The Rockefeller University
      New York City, New York, United States
  • 1999–2009
    • University of Tsukuba
      • • Institute of Basic Medical Sciences
      • • Institute of Clinical Medicine
      Tsukuba, Ibaraki-ken, Japan
  • 1997–2009
    • Northwestern University
      • Department of Cell and Molecular Biology
      Evanston, IL, United States
  • 2006
    • Babraham Institute
      Cambridge, England, United Kingdom