Insulin/IGF-1 signaling and heat stress differentially regulate HSF1 activities in germline development

Abstract

SUMMARY Germline development is sensitive to nutrient availability and environmental perturbation. Heat shock transcription factor 1 (HSF1), a key transcription factor driving the cellular heat shock response (HSR), is also involved in gametogenesis. The precise function of HSF1 (HSF-1 in C. elegans ) and its regulation in germline development are poorly understood. Using the auxin-inducible degron system in C. elegans , we uncovered a role of HSF-1 in progenitor cell proliferation and early meiosis and identified a compact but important transcriptional program of HSF-1 in germline development. Interestingly, heat stress only induces the canonical HSR in a subset of germ cells but impairs HSF-1 binding at its developmental targets. Conversely, insulin/insulin growth factor 1 (IGF-1) signaling dictates the requirement for HSF-1 in germline development and functions through repressing FOXO/DAF-16 in the soma to activate HSF-1 in germ cells. We propose that this non-cell-autonomous mechanism couples nutrient-sensing insulin/IGF-1 signaling to HSF-1 activation to support homeostasis in rapid germline growth.

Auxin-Inducible Degron System Reveals Temporal-Spatial Roles of HSF-1 and Its Transcriptional Program in Lifespan Assurance

“…Depletion of HSF-1 in the muscle also led to egg-laying defects, resulting in 100% internal hatching (20/20 animals, Supplementary Figure S5F ). It is noteworthy that none of the tissue-specific HSF-1 depletion phenocopied the L1-L2 arrest by pan-somatic depletion of HSF-1 ( Edwards et al, 2021 ), suggesting that HSF-1 functions cooperatively in all the tissue types tested to support larval development.…”

“…To examine HSF-1’s contribution to lifespan and uncouple it from its impacts on development, we took advantage of the AID system to deplete HSF-1 from the somatic tissues post-larval development. Our recent work has shown that expression of the TIR1 E3 ligase and degron tagging at the endogenous HSF-1 do not alter larval development while enabling efficient depletion of HSF-1 within 2 h of auxin treatment in adult animals ( Edwards et al, 2021 ). Depletion of HSF-1 from Day 1 in young adults shortened the median lifespan by more than one third ( Figure 1A and Table 1 ).…”

“…To better understand the molecular mechanism underlying the physiological roles of HSF-1 in lifespan, we set out to determine the transcriptional program of endogenous HSF-1 in somatic cells on Day 1 of young adults. Recently, we have determined HSF-1 binding sites specifically in the soma or the germline and binding sites used in both tissue types through whole animal ChIP-seq analyses following an acute depletion of HSF-1 in the soma or germline ( Edwards et al, 2021 ). Among those sites, 79 promoter-associated HSF-1 binding peaks are either enriched in the soma (e.g., Y94H6A.10 ) or shared by the soma and germline (e.g.…”

“…It is also different from the HSR in C. elegans, in which HSF-1 promotes both Pol II recruitment and elongation as depletion of HSF-1 either decreases Pol II across the gene (e.g., inducible hsp70s ) or causes Pol II accumulation at the promoters (e.g. hsp-110 ) during heat shock ( Edwards et al, 2021 ). The different roles of HSF-1 in transcription regulation in physiology and the HSR may be due to the fact that Pol II pausing or stalling is not prevalent in physiological conditions in C. elegans as it lacks the pausing factor NELF ( Kruesi et al, 2013 ; Maxwell et al, 2014 ).…”

“…The HSF-1 AID models were made by CRISPR knock-in of aid:gfp to the C-terminus of endogenous hsf-1 gene as detailed in our previous publication ( Edwards et al, 2021 ). New tissue-specific TIR1 models were made by modification of CA1200 ( eft-3p:tir1:mRuby ) and swapping the eft-3 promoter with tissue-specific promoters.…”