Faculty, Staff and Student Publications
Heat Shock Induces Alternative Polyadenylation Through Dynamic DNA Methylation and Chromatin Looping
Publication Date
7-1-2025
Journal
Cell Stress and Chaperones
DOI
10.1016/j.cstres.2025.100084
PMID
40412548
PMCID
PMC12162027
PubMedCentral® Posted Date
5-22-2025
PubMedCentral® Full Text Version
Post-print
Abstract
Alternative cleavage and polyadenylation (APA) is a gene regulatory mechanism used by cells under stress to upregulate proteostasis-promoting transcripts, but how cells achieve this remains poorly understood. Previously, we elucidated a DNA methylation-regulated APA mechanism, in which gene body DNA methylation enhances distal poly(A) isoform expression by blocking CCCTC-binding factor (CTCF) binding and chromatin loop formation at APA control regions. We hypothesized that DNA methylation-regulated APA is one mechanism cells employ to induce proteostasis-promoting poly(A) isoforms. At the DNAJB6 cochaperone locus, acute heat shock resulted in binding of stress response transcription factors heat shock factor 1, ATF6, and YY1 at the APA control region and an increase in the expression of the proximal poly(A) isoform known to prevent protein aggregation. Furthermore, TET1 was recruited to rapidly demethylate DNA, facilitating CTCF binding and chromatin loop formation, thereby reinforcing preferential proximal poly(A) isoform expression. As cells recovered, the transcription factors vacated the APA control region, and DNMT1 was recruited to remethylate the region. This process resolved chromatin looping and reset the poly(A) isoform expression pattern. Our findings unveil an epigenetic mechanism enabling cells to dynamically modulate poly(A) isoforms in response to stress while shedding light on the interplay between DNA methylation, transcription factor binding, and chromatin looping.
Keywords
DNA Methylation, Heat-Shock Response, Polyadenylation, Chromatin, Humans, CCCTC-Binding Factor, HSP40 Heat-Shock Proteins
Published Open-Access
yes
Recommended Citation
Fink, Emily E; Zhang, Yi; Santo, Briana; et al., "Heat Shock Induces Alternative Polyadenylation Through Dynamic DNA Methylation and Chromatin Looping" (2025). Faculty, Staff and Student Publications. 4699.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4699
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