Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. Several lines of evidence also link HDACs to cancer. HDAC inhibitors in combination with other therapeutic agents have shown promise in preclinical trials for the treatment of leukemias and solid tumors. HDAC1 and HDAC2 are highly conserved enzymes and both are present in repressor complexes, such as Sin3, NuRD and CoREST complexes. Hematopoietic specific transcription factor GATA-1 is essential for hematopoietic development. Misregulation of GATA-1 is linked to hematologic diseases including leukemia. The activity of GATA-1 is regulated through its associated cofactors and is required for erythroid differentiation. However, GATA-1 remains associated with HDAC1 containing corepressor complexes during differentiation of erythroid cells. We found that GATA-1 associated HDAC1 has increased acetylation modification during erythroid differentiation. We previously found that HDAC1 can be acetylated and that acetylated HDAC1 completely lost deacetylase activity (Qiu et al, 2006). In addition, acetylated HDAC1 inhibits the deacetylase activity through forming inactive dimers (Luo et al., 2009). These observations indicate a novel but rather general regulation mechanism of histone deacetylase containing complexes. In this proposal, we investigate two important aspects of HDAC1 function: How are HDAC1 containing corepressor complexes regulated through HDAC1 acetylation modification and how are they regulated during erythroid differentiation? We hypothesize that HDAC1 acetylation inhibits deacetylase activity of HDAC1 and HDAC2, thereby downregulating the corepressor complex activity. In addition, this process is important for GATA-1 mediated erythroid differentiation. These studies will allow us to understand the molecular basis of the regulation of deacetylation of HDACs and the roles they play in hematopoiesis and general transcription regulation. In addition, understanding the structural and functional differences between HDAC1 and HDAC2 might shed light on new strategies for the development of isoform specific inhibitors for HDAC1 or 2 that can be used in the treatment of leukemia and other cancer.

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Histone deacetylases (HDACs) play important roles in the transcriptional regulation of eukaryotic cells. In this project, we will try to understand how the deacetylase activity of HDAC1 associated corepressor complexes is regulated by HDAC1 acetylation. We will also study how this regulation impacts hematopoiesis and GATA-1 mediated transcription.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hematopoiesis Study Section (HP)
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Thomas, John
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University of Florida
Anatomy/Cell Biology
Schools of Medicine
United States
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Jian, Wei; Yan, Bowen; Huang, Suming et al. (2017) Histone deacetylase 1 activates PU.1 gene transcription through regulating TAF9 deacetylation and transcription factor IID assembly. FASEB J 31:4104-4116
Deng, Changwang; Li, Ying; Zhou, Lei et al. (2016) HoxBlinc RNA Recruits Set1/MLL Complexes to Activate Hox Gene Expression Patterns and Mesoderm Lineage Development. Cell Rep 14:103-114
Li, Ying; Schulz, Vincent P; Deng, Changwang et al. (2016) Setd1a and NURF mediate chromatin dynamics and gene regulation during erythroid lineage commitment and differentiation. Nucleic Acids Res 44:7173-88
Yang, H; Yan, B; Liao, D et al. (2015) Acetylation of HDAC1 and degradation of SIRT1 form a positive feedback loop to regulate p53 acetylation during heat-shock stress. Cell Death Dis 6:e1747
Salz, Tal; Deng, Changwang; Pampo, Christine et al. (2015) Histone Methyltransferase hSETD1A Is a Novel Regulator of Metastasis in Breast Cancer. Mol Cancer Res 13:461-9
Tusi, Betsabeh Khoramian; Deng, Changwang; Salz, Tal et al. (2015) Setd1a regulates progenitor B-cell-to-precursor B-cell development through histone H3 lysine 4 trimethylation and Ig heavy-chain rearrangement. FASEB J 29:1505-15
Li, Xuehui; Yang, Hui; Huang, Suming et al. (2014) Histone deacetylase 1 and p300 can directly associate with chromatin and compete for binding in a mutually exclusive manner. PLoS One 9:e94523
Patel, B; Kang, Y; Cui, K et al. (2014) Aberrant TAL1 activation is mediated by an interchromosomal interaction in human T-cell acute lymphoblastic leukemia. Leukemia 28:349-61
Salz, Tal; Li, Guangyao; Kaye, Frederic et al. (2014) hSETD1A regulates Wnt target genes and controls tumor growth of colorectal cancer cells. Cancer Res 74:775-86
Yang, Hui; Salz, Tal; Zajac-Kaye, Maria et al. (2014) Overexpression of histone deacetylases in cancer cells is controlled by interplay of transcription factors and epigenetic modulators. FASEB J 28:4265-79

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