E2F coregulates an essential HSF developmental program that is distinct from the heat-shock response

Abstract

Heat-shock factor (HSF) is the master transcriptional regulator of the heat-shock response (HSR) and is essential for stress resilience. HSF is also required for metazoan development; however, its function and regulation in this process are poorly understood. Here, we characterize the genomic distribution and transcriptional activity of Caenorhabditis elegans HSF-1 during larval development and show that the developmental HSF-1 transcriptional program is distinct from the HSR. HSF-1 developmental activation requires binding of E2F/DP to a GC-rich motif that facilitates HSF-1 binding to a heat-shock element (HSE) that is degenerate from the consensus HSE sequence and adjacent to the E2F-binding site at promoters. In contrast, induction of the HSR is independent of these promoter elements or E2F/DP and instead requires a distinct set of tandem canonical HSEs. Together, E2F and HSF-1 directly regulate a gene network, including a specific subset of chaperones, to promote protein biogenesis and anabolic metabolism, which are essential in development.

Mitochondrial Stress Restores the Heat Shock Response and Prevents Proteostasis Collapse during Aging

“…Therefore we asked whether F29C4.2(0.2)(RNAi) could enhance the levels of HSF-1 and RNA Pol II at HSR promoters using animals expressing a single copy of HSF-1::GFP (Li et al, 2016). HSF-1::GFP animals exhibit an enhanced HSR and stress resistance in response to F29C4.2(0.2)(RNAi) (Figure S3J and K).…”

“…Given that the transcription factor HSF-1 is central to the HSR, stress resistance, and cytosolic proteostasis (Akerfelt et al, 2010; Li, Labbadia and Morimoto, 2017), we asked whether the beneficial effects of mitochondrial stress require HSF-1. Therefore, we examined survival following HS in animals exposed to L4440 or F29C4.2(0.2)(RNAi) in combination with hsf-1(RNAi) or atfs-1(RNAi) , and in hsf-1(sy441) and atfs-1(tm4525) mutants that have a diminished HSR and UPR mt respectively (Bennett et al, 2014; Li et al, 2016; Nargund et al., 2015). Both RNAi mediated knock-down and loss of function mutations in hsf-1 and atfs-1 severely dampened the ability of F29C4.2(0.2)(RNAi) to induce stress response genes and fluorescent reporters associated with the HSR and UPR mt , thereby demonstrating that HSF-1 and ATFS-1 are essential for F29C4.2(0.2)RNAi to enhance the HSR and UPR mt respectively (Figure S5A-D).…”

Rethinking HSF1 in Stress, Development, and Organismal Health

“…However, accumulating evidence in metazoans have challenged these traditional views and suggest that the HSR is tailored to specific cellular needs and regulated by cell-non-autonomous control through communication between tissues [23–25]. Further, HSF1 directs transcriptional programs in development and metabolism [26, 27] that are distinct from the classical HSR. These non-canonical HSF1 transcriptional programs influence the PN and other cellular functions in aging and disease in addition to the HSR [25, 28].…”

“…However, there is now increasing evidence from a number of biological systems that HSF1 is important for diverse “non-stress” conditions including development [26, 40], energy metabolism [27], programmed cell death [41, 42] and carcinogenesis [28, 43]. For these non-heat shock conditions, the transcriptomes regulated by HSF1 are distinct from that of acute heat shock [26, 40]. It is, therefore, important to understand mechanistically how HSF1 regulates these alternative transcriptional programs to influence long-term cellular health.…”

“…HSF1 is a single copy gene in C. elegans and Drosophila and is essential for growth and development [26, 44]. In addition, HSF1 is the major regulator of the HSR among multiple HSFs expressed in mammals, and is a maternal factor required for gametogenesis in mice [45].…”