HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis.
HDAC1 is required for GATA-1 transcription activity, global chromatin occupancy and hematopoiesis.
复制标题
DOI：
10.1093/nar/gkab737
复制
发表时间：
2021-09-27
影响因子：
14.9
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Yan B;Yang J;Kim MY;Luo H;Cesari N;Yang T;Strouboulis J;Zhang J;Hardison R;Huang S;Qiu Y
造血因子GATA-1的活性通过p300/ cbp介导的乙酰化和fog1介导的与含有NuRD复合物的HDAC1/2的间接相互作用来调节。尽管GATA-1乙酰化与GATA-1激活有关，但未研究去乙酰化的作用。在这里，我们发现fog1 /NuRD不会使GATA-1脱乙酰。然而，hdac /2可以直接结合GATA-1并使其去乙酰化。GATA-1连接区域内的两个精氨酸残基介导与HDAC1的直接相互作用。精氨酸转丙氨酸突变（2RA）阻断GATA-1去乙酰化，不能诱导红细胞分化。基因表达谱和ChIP-seq分析进一步证明了GATA-1去乙酰化对基因激活和染色质募集的重要性。GATA-12RA敲入（KI）小鼠患有轻度贫血和血小板减少症，骨髓和脾脏中未成熟红细胞和巨核细胞积聚。Lin - cKit+ (LK)细胞的单细胞RNA-seq分析进一步揭示了KI小鼠HSC、髓系祖细胞和红细胞/巨核细胞簇中细胞亚群和特征基因表达模式的深刻变化。因此，GATA-1去乙酰化及其与HDAC1的相互作用调节GATA-1染色质结合和转录活性，从而控制红/巨核细胞的承诺和分化。
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.