Heat shock transcription factor 1 (HSF1) is a highly versatile transcription factor that, in addition to protecting cells against proteotoxic stress, is also critical during diverse developmental processes. Although the functions of HSF1 have received considerable attention, its potential role in β-globin gene regulation during erythropoiesis has not been fully elucidated. Here, after comparing the transcriptomes of erythrocytes differentiated from cord blood or adult peripheral blood hematopoietic progenitor CD34+ cells in vitro, we constructed the molecular regulatory network associated with β-globin genes and identified novel and putative globin gene regulators by combining the weighted gene coexpression network analysis (WGCNA) and context likelihood of relatedness (CLR) algorithms. Further investigation revealed that one of the identified regulators, HSF1, acts as a key activator of the γ-globin gene in human primary erythroid cells in both erythroid developmental stages. While during stress, HSF1 is required for heat-induced globin gene activation, and HSF1 downregulation markedly decreases globin gene induction in K562 cells. Mechanistically, HSF1 occupies DNase I hypersensitive site 3 of the locus control region upstream of β-globin genes via its canonical binding motif. Hence, HSF1 executes stress-dependent and -independent roles in fetal γ-globin regulation during erythroid differentiation.

中文翻译：

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热激转录因子1在红系分化过程中以应力依赖和独立的方式调节胎儿γ-珠蛋白的表达。

热休克转录因子1（HSF1）是一种高度通用的转录因子，除了保护细胞免受蛋白毒性压力外，在各种发育过程中也至关重要。尽管HSF1的功能受到了广泛的关注，但尚未充分阐明其在红细胞生成过程中β-珠蛋白基因调控中的潜在作用。在这里，我们在体外比较了从脐带血或成年外周血造血祖细胞CD34 +细胞分化出的红细胞的转录组后，我们构建了与β-珠蛋白基因相关的分子调控网络，并通过结合加权基因共表达网络确定了新型和假定的珠蛋白基因调控因子。分析（WGCNA）和关联可能性（CLR）算法。进一步的研究表明，已确定的调节剂之一HSF1在两个类红细胞发育阶段均是人原代红细胞中γ-珠蛋白基因的关键激活剂。在压力期间，HSF1是热诱导的球蛋白基因激活所必需的，而HSF1的下调显着降低了K562细胞中球蛋白基因的诱导。从机制上讲，HSF1通过其规范的结合基序占据了β-珠蛋白基因上游基因座控制区的DNase I超敏位点3。因此，HSF1在红系分化过程中在胎儿γ珠蛋白调节中执行压力依赖性和非依赖性作用。HSF1的下调显着降低K562细胞中的球蛋白基因诱导。从机制上讲，HSF1通过其规范的结合基序占据了β-珠蛋白基因上游基因座控制区的DNase I超敏位点3。因此，HSF1在红系分化过程中在胎儿γ珠蛋白调节中执行压力依赖性和非依赖性作用。HSF1的下调显着降低K562细胞中的球蛋白基因诱导。从机制上讲，HSF1通过其规范的结合基序占据了β-珠蛋白基因上游基因座控制区的DNase I超敏位点3。因此，HSF1在红系分化过程中在胎儿γ珠蛋白调节中执行压力依赖性和非依赖性作用。