HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis

TY - JOUR

T1 - HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis

AU - Yan, Bowen

AU - Yang, Jennifer

AU - Kim, Min Young

AU - Luo, Huacheng

AU - Cesari, Nicholas

AU - Yang, Tao

AU - Strouboulis, John

AU - Zhang, Jiwang

AU - Hardison, Ross

AU - Huang, Suming

AU - Qiu, Yi

N1 - Publisher Copyright: © 2021 The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.

PY - 2021/9/27

Y1 - 2021/9/27

N2 - The activity of hematopoietic factor GATA-1 is modulated through p300/CBP-mediated acetylation and FOG-1 mediated indirect interaction with HDAC1/2 containing NuRD complex. Although GATA-1 acetylation is implicated in GATA-1 activation, the role of deacetylation is not studied. Here, we found that the FOG-1/NuRD does not deacetylate GATA-1. However, HDAC1/2 can directly bind and deacetylate GATA-1. Two arginine residues within the GATA-1 linker region mediates direct interaction with HDAC1. The arginine to alanine mutation (2RA) blocks GATA-1 deacetylation and fails to induce erythroid differentiation. Gene expression profiling and ChIP-seq analysis further demonstrate the importance of GATA-1 deacetylation for gene activation and chromatin recruitment. GATA-12RA knock-in (KI) mice suffer mild anemia and thrombocytopenia with accumulation of immature erythrocytes and megakaryocytes in bone marrow and spleen. Single cell RNA-seq analysis of Lin- cKit+ (LK) cells further reveal a profound change in cell subpopulations and signature gene expression patterns in HSC, myeloid progenitors, and erythroid/megakaryocyte clusters in KI mice. Thus, GATA-1 deacetylation and its interaction with HDAC1 modulates GATA-1 chromatin binding and transcriptional activity that control erythroid/megakaryocyte commitment and differentiation.

AB - The activity of hematopoietic factor GATA-1 is modulated through p300/CBP-mediated acetylation and FOG-1 mediated indirect interaction with HDAC1/2 containing NuRD complex. Although GATA-1 acetylation is implicated in GATA-1 activation, the role of deacetylation is not studied. Here, we found that the FOG-1/NuRD does not deacetylate GATA-1. However, HDAC1/2 can directly bind and deacetylate GATA-1. Two arginine residues within the GATA-1 linker region mediates direct interaction with HDAC1. The arginine to alanine mutation (2RA) blocks GATA-1 deacetylation and fails to induce erythroid differentiation. Gene expression profiling and ChIP-seq analysis further demonstrate the importance of GATA-1 deacetylation for gene activation and chromatin recruitment. GATA-12RA knock-in (KI) mice suffer mild anemia and thrombocytopenia with accumulation of immature erythrocytes and megakaryocytes in bone marrow and spleen. Single cell RNA-seq analysis of Lin- cKit+ (LK) cells further reveal a profound change in cell subpopulations and signature gene expression patterns in HSC, myeloid progenitors, and erythroid/megakaryocyte clusters in KI mice. Thus, GATA-1 deacetylation and its interaction with HDAC1 modulates GATA-1 chromatin binding and transcriptional activity that control erythroid/megakaryocyte commitment and differentiation.

UR - http://www.scopus.com/inward/record.url?scp=85117402357&partnerID=8YFLogxK

U2 - 10.1093/nar/gkab737

DO - 10.1093/nar/gkab737

M3 - Article

C2 - 34450641

AN - SCOPUS:85117402357

SN - 0305-1048

VL - 49

SP - 9783

EP - 9798

JO - Nucleic Acids Research

JF - Nucleic Acids Research

IS - 17

ER -