Heat shock transcription factor 1 regulates the fetal γ-globin expression in a stress-dependent and independent manner during erythroid differentiation.

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.