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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL095674-03
Application #
8309145
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2010-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
3
Fiscal Year
2012
Total Cost
$362,588
Indirect Cost
$115,088
Name
University of Florida
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611