Heat shock factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat shock response

• Published in: Cell reports (Cambridge) Vol. 42; no. 6; p. 112557
• Main Authors: Xu, Meng, Lin, Ling, Ram, Babul Moni, Shriwas, Omprakash, Chuang, Kun-Han, Dai, Siyuan, Su, Kuo-Hui, Tang, Zijian, Dai, Chengkai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.06.2023; Elsevier
• Subjects: c-MYC; CP: Molecular biology; CUT&RUN-seq; GCN5; HSF1; transcription factor complex; transcription factor complex; CP: Molecular biology; GCN5; CUT&RUN-seq; c-MYC; HSF1
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112557

Despite its pivotal roles in biology, how the transcriptional activity of c-MYC is tuned quantitatively remains poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat shock response, acts as a prime modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome wide. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on genomic DNAs, and surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase general control nonderepressible 5 (GCN5), promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, we find that HSF1 specifically potentiates the c-MYC-mediated transcription, discrete from its canonical role in countering proteotoxic stress. 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. [Display omitted] •c-MYC and HSF1 comprise a transcription factor complex without heat stress•HSF1 physically couples c-MYC and GCN5 to promote histone acetylation•HSF1 association strengthens the genome-wide DNA binding of c-MYC•HSF1 augments the c-MYC-mediated transcriptional program Xu et al. find that, under non-stressed conditions, HSF1, c-MYC, and MAX constitute a transcription factor complex, in sharp contrast with the assembly of HSF1 homotrimers during the heat shock response. HSF1 exerts a non-canonical transcriptional action in the absence of proteotoxic stress, amplifying c-MYC-mediated transcription genome wide.