Gene Bookmarking by the Heat-Shock Transcription Factor Programs the Insulin-Like Signaling Pathway

Abstract

Early-life stress exposure alters the risk of chronic late-life disease. To understand how this occurs, we examined how activation of the universal and conserved stress-responsive transcription factor, HSF-1 in C. elegans germ cells alters proteostasis and survival programs of these germ cells following their fertilization and development into adults. Surprisingly, we found that upon germline activation, HSF-1 negatively bookmarks the insulin-receptor daf-2 and other HSF-1 target genes by recruiting the conserved histone 3 lysine 9 (H3K9) methyltransferase MET-2 and increasing repressive H3K9me2 levels at these genomic loci. Increased H3K9me2 persists in adults decreasing their stress responsivity but enhancing stress resilience through the activation of the FOXO ortholog, DAF-16. Thus, paradoxically, HSF-1 recruits the germline machinery normally responsible for erasing germline transcriptional memory, but instead, establishes a heritable epigenetic memory of prior stress exposure. These studies provide a mechanism by which early-life stress exposure heritably alters later-life proteostasis and stress responses.