The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.
The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.
复制标题
DOI：
10.1093/nar/gkad167
复制
发表时间：
2023-06-09
影响因子：
14.9
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Wang, Zi;Wang, Pan;Zhang, Jieying;Gong, Han;Zhang, Xuchao;Song, Jianhui;Nie, Ling;Peng, Yuanliang;Li, Yanan;Peng, Hongling;Cui, Yajuan;Li, Heng;Hu, Bin;Mi, Jun;Liang, Long;Liu, Hong;Zhang, Ji;Ye, Mao;Yazdanbakhsh, Karina;Mohandas, Narla;An, Xiuli;Han, Xu;Liu, Jing
正常的红细胞生成需要基因表达模式的精确调控，转录辅因子在这一过程中起着至关重要的作用。辅助因子的失调已经成为红系疾病的关键机制。通过基因表达谱分析，我们发现HES 6作为一个丰富的辅因子在人类红细胞生成过程中在基因水平上表达。HES 6与GATA 1发生物理相互作用，并影响GATA 1与FOG 1的相互作用。HES 6的敲低通过降低GATA 1表达损害人红细胞生成。染色质免疫沉淀和RNA测序揭示了一组丰富的HES 6和GATA 1共调控基因参与红细胞相关途径。我们还发现了一个由HES 6、GATA 1和STAT 1组成的正反馈回路，参与红细胞生成的调控。值得注意的是，促红细胞生成素（EPO）刺激导致这些环组件的上调。在真性红细胞增多症患者的CD 34+细胞中观察到环组分的表达水平增加。通过HES 6敲低或STAT 1活性抑制的干扰抑制了具有JAK 2 V617 F突变的红系细胞的增殖。我们进一步探索了HES 6对小鼠中真性红细胞增多症表型的影响。HES 6-GATA 1调节环的鉴定及其通过EPO的调节为EPO/EPOR调节的人类红细胞生成提供了新的见解，并为真性红细胞增多症的管理提供了潜在的治疗靶点。HES 6作为GATA 1辅因子促进红细胞生成。HES 6、GATA 1和STAT 1在正常红细胞生成中形成正反馈环。这个激活的环是真性红细胞增多症的潜在靶点。
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 JAK2V617F 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. HES6 as a GATA1 cofactor facilitated erythropoiesis. HES6, GATA1 and STAT1 formed a positive feedback loop in normal erythropoiesis. This activated loop was a potential target in polycythemia vera.
登录
查看更多内容
影响因子：
20.3
作者：
Halupa, A;Bailey, ML;Barber, DL
通讯作者：
Barber, DL
影响因子：
4.8
作者：
Eun, Bokkee;Lee, Yool;Kim, Hyun
通讯作者：
Kim, Hyun
影响因子：
8
作者：
Cantor, AB;Orkin, SH
通讯作者：
Orkin, SH
影响因子：
7.4
作者：
Cokic VP;Bhattacharya B;Beleslin-Cokic BB;Noguchi CT;Puri RK;Schechter AN
通讯作者：
Schechter AN
影响因子：
30.8
作者：
Basak, Anindita;Munschauer, Mathias;Sankaran, Vijay G.
通讯作者：
Sankaran, Vijay G.