Regulation of HDAC1 Histone Deacetylase Activity During Hematopoesis
Authors: Yang Tao , Lou Yi , Jian Wei , Bungert Jorg , Noguchi Constance Tom , Huang Suming , Qiu Yi 
Published: October 2019

Abstract
Abstract 3869
Histone deacetylases (HDACs) play important roles in transcriptional regulation in eukaryotic cells. HDAC1 has been implicated in diverse cellular processes, such as developmental programming, gene expression and cell cycle progression, which are often linked to epigenetic repression. However, emerging evidence also suggests that histone deacetylase activity may be required for transcriptional activation. HDAC1 and its closely related protein HDAC2 are often present in repressor complexes, such as Sin3, NuRD and CoREST complexes. HDAC1 can undergo post transcription modifications, such as phosphorylation, sumoylation and acetylation. Acetylated HDAC1 lost deacetylase activity. Importantly, acetylated HDAC1 also inhibit the deacetylase activity of HDAC2, hence to down regulate the overall deacetylase activity of HDAC1/2 containing complexes. It is shown that NuRD corepressor complexes are important in regulating GATA-1 function during erythroid differentiation. However, it is not clear how histone deacetylase activity affects NuRD complex activity and influence hematopoiesis. In this study, we investigate the role of HDAC1 during erythroid differentiation. We tested HDAC1 level and activity in G1E-ER4 cells. G1E is a GATA-1 null erythroid progenitor cells. G1E-ER4 cells were engineered to stably express estrogen inducible GATA-1. Addition of estrogen leads to rapid induction of erythroid differentiation. HDAC1 deacetylase activity decreased upon treatment of estrogen. However, the HDAC1 protein level remains unchanged, suggesting that HDAC1 deacetylase activity, but not its protein level, is regulated. Accordingly, we found that acetylated HDAC1 level increased. Consistent with this observation, acetylated HDAC1 also increase upon Epo induction in human CD34+ cells. These results suggest that HDAC1 acetylation regulates the deacetylase activity during erythroid differentiation. To further test the role of HDAC1 in erythroid differentiation, we generated stable HDAC1 and HDAC2 knock down cell lines from MEL cells. The results show that HDAC1 and HDAC2 knock down inhibit differentiation and promote proliferation. To test the role of acetylated HDAC1 in differentiation, stable cell lines that over express HDAC1 and mutants mimicking acetylated or unacetylated HDAC1 were established. The cells that over express acetylated HDAC1 promote differentiation and cells that overexpress non acetylatable HDAC1 inhibit differentiation. We further studied whether HDAC1 modulates erythroid differentiation through regulating the activity of key erythroid transcription factor GATA-1. It is suggested that GATA-1 mediates gene activation through its association with coactivator complexes. However, recent studies indicated that GATA-1 associates with HDAC1/2 containing corepressor complexes (NuRD) throughout differentiation of erythroid cells. We investigated GATA-1 associated deacetylase activity during erythroid differentiation. We found that the deacetylase activity of the complex decreased and further diminished at during differentiation, coordinately with the increase of acetylated form of HDAC1 in both Mel cells and G1E-ER4 cells. We further demonstrated the role of HDAC1 in GATA-1 mediated gene transcription in reporter assays. These studies indicate that HDAC1 plays an important role in regulating GATA-1 activity and the deacetylase activity of the GATA-1 associated NuRD complex is also regulated. This complex may play differential roles in undifferentiated and differentiated erythroid cells. Thus, our results suggest a novel but rather general regulatory mechanism of histone deacetylase containing protein complexes.

Disclosures:
No relevant conflicts of interest to declare.