The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.

Nucleic acids research 2023 Mar 17

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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. © The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

Citation

Zi Wang, Pan Wang, Jieying Zhang, Han Gong, Xuchao Zhang, Jianhui Song, Ling Nie, Yuanliang Peng, Yanan Li, Hongling Peng, Yajuan Cui, Heng Li, Bin Hu, Jun Mi, Long Liang, Hong Liu, Ji Zhang, Mao Ye, Karina Yazdanbakhsh, Narla Mohandas, Xiuli An, Xu Han, Jing Liu. The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis. Nucleic acids research. 2023 Mar 17;51(10):4774-4790