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.

中文翻译：

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新型 GATA1 相互作用蛋白 HES6 是人类红细胞生成的重要转录辅助因子


正常的红细胞生成需要基因表达模式的精确调控，转录辅助因子在此过程中发挥着至关重要的作用。辅助因子的失调已成为导致红细胞疾病的关键机制。通过基因表达谱分析，我们发现 HES6 作为人类红细胞生成过程中在基因水平表达的丰富辅因子。 HES6 与 GATA1 发生物理相互作用，并影响 GATA1 与 FOG1 的相互作用。 HES6 的敲低通过降低 GATA1 表达来损害人类红细胞生成。染色质免疫沉淀和 RNA 测序揭示了一组丰富的 HES6 和 GATA1 共同调控的基因，这些基因参与红细胞相关途径。我们还发现了一个由 HES6、GATA1 和 STAT1 组成的红细胞生成调节正反馈环。值得注意的是，促红细胞生成素（EPO）刺激导致这些环成分的上调。在真性红细胞增多症患者的 CD34+ 细胞中观察到环成分的表达水平增加。通过敲低 HES6 或抑制 STAT1 活性来干扰 JAK2V617F 突变的红系细胞的增殖。我们进一步探讨了 HES6 对小鼠真性红细胞增多症表型的影响。 HES6-GATA1 调节环及其受 EPO 调节的鉴定为 EPO/EPOR 调节的人类红细胞生成提供了新的见解，并为治疗真性红细胞增多症提供了潜在的治疗靶点。