Transcriptional response to stress in the dynamic chromatin environment of cycling and mitotic cells

Abstract

Heat shock factors (HSFs) are the master regulators of transcription under protein-damaging conditions, acting in an environment where the overall transcription is silenced. We determined the genomewide transcriptional program that is rapidly provoked by HSF1 and HSF2 under acute stress in human cells. Our results revealed the molecular mechanisms that maintain cellular homeostasis, including HSF1-driven induction of polyubiquitin genes, as well as HSF1-and HSF2-mediated expression patterns of cochaperones, transcriptional regulators, and signaling molecules. We characterized the genomewide transcriptional response to stress also in mitotic cells where the chromatin is tightly compacted. We found a radically limited binding and transactivating capacity of HSF1, leaving mitotic cells highly susceptible to proteotoxicity. In contrast, HSF2 occupied hundreds of loci in the mitotic cells and localized to the condensed chromatin also in meiosis. These results highlight the importance of the cell cycle phase in transcriptional responses and identify the specific mechanisms for HSF1 and HSF2 in transcriptional orchestration. Moreover, we propose that HSF2 is an epigenetic regulator directing transcription throughout cell cycle progression.ChIP-seq | ENCODE | human genome | proteostasis C ells exposed to proteotoxic conditions provoke a rapid and transient response to maintain homeostasis. The stress response induces profound cellular adaptation as cytoskeleton and membranes are reorganized, cell cycle progression is stalled, and the global transcription and translation are silenced (1, 2). Despite the silenced chromatin environment, the stressed cell mounts a transcriptional program that involves induction of genes coding for heat shock proteins (HSPs). HSPs are molecular chaperones and proteases that assist in protein folding and maintain cellular structures and molecular functions (3).Heat shock factor 1 (HSF1) is an evolutionarily well-conserved transcription factor that is rapidly activated by stress and absolutely required for the stress-induced HSP expression (4). Aberrant HSF1 levels are associated with stress sensitivity, aging, neurodegenerative diseases, and cancer (5-9). Instead of a single HSF in yeasts and invertebrates, vertebrates contain a family of four members, HSF1-4. HSF2 and HSF4 are involved in corticogenesis, spermatogenesis, and formation of sensory epithelium, and they have primarily been considered as developmental factors (10-14). HSF1 and HSF2 share high sequence homology of the DNA-binding and oligomerization domains and are able to form heterotrimers at the chromatin (15, 16). Moreover, HSF2 participates in the regulation of stress-responsive genes and is required for proper protein clearance also at febrile temperatures (17,18). Although HSF1 and HSF2 have been shown to interplay on the heat shock elements (HSEs) of the target loci, their impacts on transcription of chaperone genes are remarkably different; HSF1 is a potent inducer of transcription, whereas HSF2 is a poor transactivator o...

Human NF-κB repressing factor acts as a stress-regulated switch for ribosomal RNA processing and nucleolar homeostasis surveillance

“…Analysis of genome-wide ChIP-seq data (Gene Expression Omnibus accession no. GSE43579) also confirmed that NKRF is included in the 1,242 HSF1 target genes identified during heat stress in a different type of human cell (K562 erythroleukemia) (18). Interestingly, in addition to heat, HSF1 activation during proteotoxic stress induced by arsenite or proteasome inhibition also triggered NKRF expression, whereas endoplasmic reticulum (ER) stress inducers thapsigargin and tunicamycin had no effect (Fig.…”

Effects of intrinsic aerobic capacity, aging and voluntary running on skeletal muscle sirtuins and heat shock proteins

“…HSFs activate the transcription of a large number of genes that regulate protein homeostasis, including genes encoding heat shock proteins Hsp27 and Hsp70 Vihervaara et al, 2013). Hsp10 typically functions as chaperone in mitochondria together with Hsp60 (Jia et al, 2011).…”

Genomic Heat Shock Element Sequences Drive Cooperative Human Heat Shock Factor 1 DNA Binding and Selectivity

“…The large thermal shifts observed provide indirect evidence that HSF1-HSE interactions are stable, consistent with the idea that dissociation of HSF1 from DNA in vivo may require acetylation of HSF1 on lysine 80 within the DNA binding domain (30) or other active processes. (15,16,23,24). To understand the influence of HSE variation on the HSF1-binding site selection,…”

“…To address this question, a set of genomic HSEs recently identified in human K562 cells by comprehensive ChIP-seq experiments was evaluated for HSF1 binding in vitro (15). In this study, some genomic HSE sequences were bound by HSF1, although others were bound only by the related transcription factor HSF2.…”

“…1A) (3,14). Importantly, although the consensus HSE sequence is well characterized, an enormous variety of HSEs exists throughout the human genome, which vary in their primary sequence, length, and orientation of nGAAn repeats (15,16). A striking example of this diversity is the satellite III repeat region of chromosome 9 in human cells, which serves as a template for the noncoding satellite III RNA involved in the stress response.…”