Heat shock factor 1 specifically potentiates c-MYC-mediated transcription independently of the canonical heat-shock response

Despite its pivotal roles in biology, how the transcriptional activity of c-MYC is attuned quantitatively remain poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat-shock response, acts as a key modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome-widely. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on DNAs and, surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase GCN5, thereby promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, our studies reveal that HSF1 specifically potentiates the c-MYC-mediated transcription, distinct from its role in the canonical heat-shock response. Importantly, this mechanism of action engenders two distinct c-MYC activation states, primary and advanced, which may be important to accommodate diverse physiological and pathological conditions. To elucidate the impact of HSF1 on the c-MYC-mediated transcriptional program, we compared the genome occpancy of c-MYC between Hsf1 WT and Hsf1 CKO mouse embryonic fibroasts (MEFs) by CUT&RUN-seq with E Coli spike-in normalization control. Furthermore, we compared the gene expression between MEFs transfected with control siRNAs and MEFs transfected with Hsf1-targeting siRNAs by RNA-seq with ERCC ExFold spike-in normalization control.