Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis. HES6 physically interacted with GATA1 and influenced the interaction of GATA1 with FOG1. Knockdown of HES6 impaired human erythropoiesis by decreasing GATA1 expression. Chromatin immunoprecipitation and RNA sequencing revealed a rich set of HES6- and GATA1-co-regulated genes involved in erythroid-related pathways. We also discovered a positive feedback loop composed of HES6, GATA1 and STAT1 in the regulation of erythropoiesis. Notably, erythropoietin (EPO) stimulation led to up-regulation of these loop components. Increased expression levels of loop components were observed in CD34(+) cells of polycythemia vera patients. Interference by either HES6 knockdown or inhibition of STAT1 activity suppressed proliferation of erythroid cells with the JAK2(V617F) mutation. We further explored the impact of HES6 on polycythemia vera phenotypes in mice. The identification of the HES6-GATA1 regulatory loop and its regulation by EPO provides novel insights into human erythropoiesis regulated by EPO/EPOR and a potential therapeutic target for the management of polycythemia vera.
基金：
This work was supported by the National Natural
Science Foundation of China [81920108004, 81770107,81702722, 81470362, 81870105, 92253201, 82070175 and
U1804282]; the Natural Science Foundation of Hunan
Province [2022JJ30787 and 2022JJ30830]; the Science
and Technology Key Project of Hunan Province
[2018SK21212]; the Scientific Research Fund Project of
Hunan Provincial Health Commission [20201921]; Central
South University Innovation-Driven Research Programme
[2023CXQD015]; Fundamental Research Funds
for the Central Universities of Central South University
[2021zzts0085 and 2021zzts0562]; Natural Science Foundation
of Changsha City [kq2202121]; the National Institute
of Health [HL149626 and HL140625] and Postgraduate
Scientific Research Innovation Project of Hunan Province
[CX20220132].
第一作者机构：[1]Cent South Univ, Xiangya Hosp 2, Dept Hematol, Shanghai, Peoples R China[2]Mol Biol Res Ctr, Ctr Med Genet, Sch Life Sci, Shanghai, Peoples R China[3]Cent South Univ, Hunan Prov Key Lab Basic & Appl Hematol, Changsha 410011, Peoples R China
共同第一作者：
通讯作者：
通讯机构：[1]Cent South Univ, Xiangya Hosp 2, Dept Hematol, Shanghai, Peoples R China[2]Mol Biol Res Ctr, Ctr Med Genet, Sch Life Sci, Shanghai, Peoples R China[3]Cent South Univ, Hunan Prov Key Lab Basic & Appl Hematol, Changsha 410011, Peoples R China
推荐引用方式(GB/T 7714)：
Wang Zi,Wang Pan,Zhang Jieying,et al.The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis[J].NUCLEIC ACIDS RESEARCH.2023,51(10):4774-4790.doi:10.1093/nar/gkad167.
APA：
Wang, Zi,Wang, Pan,Zhang, Jieying,Gong, Han,Zhang, Xuchao...&Liu, Jing.(2023).The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.NUCLEIC ACIDS RESEARCH,51,(10)
MLA：
Wang, Zi,et al."The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis".NUCLEIC ACIDS RESEARCH 51..10(2023):4774-4790
生物学