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Heat stress (HS) induces a cellular response leading to profound changes in gene expression. Here, we show that human YTHDC1, a reader of N 6 -methyladenosine (m 6 A) RNA modification, mostly associates to the chromatin fraction and that HS induces a redistribution of YTHDC1 across the genome, including to heat-induced heat shock protein (HSP) genes. YTHDC1 binding to m 6 A-modified HSP transcripts co-transcriptionally promotes expression of HSPs. In parallel, hundreds of the genes enriched in YTHDC1 during HS have their transcripts undergoing YTHDC1- and m 6 A-dependent intron retention. Later, YTHDC1 concentrates within nuclear stress bodies (nSBs) where it binds to m 6 A-modified SATIII non-coding RNAs, produced in an HSF1-dependent manner upon HS. These findings reveal that YTHDC1 plays a central role in a chromatin-associated m 6 A-based reprogramming of gene expression during HS. Furthermore, they support the model where the subsequent and temporary sequestration of YTHDC1 within nSBs calibrates the timing of this YTHDC1-dependent gene expression reprogramming., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Epigenomic studies on humans and model species have revealed substantial inter-individual variation in histone modification profiles. However, the pattern of this variation has not been precisely characterized, particularly regarding which genomic features are enriched for variability and whether distinct histone marks co-vary synergistically. Yeast allows us to investigate intra-species variation at high resolution while avoiding other sources of variation, such as cell type or subtype. Results: We profiled histone marks H3K4me3, H3K9ac, H3K14ac, H4K12ac and H3K4me1 in three unrelated wild strains of Saccharomyces cerevisiae at single-nucleosome resolution and analyzed inter-strain differences statistically. All five marks varied significantly at specific loci, but to different extents. The number of nucleosomes varying for a given mark between two strains ranged from 20 to several thousands; +1 nucleosomes were significantly less subject to variation. Genes with highly evolvable or responsive expression showed higher variability; however, the variation pattern could not be explained by known transcriptional differences between the strains. Synergistic variation of distinct marks was not systematic, with surprising differences between functionally related H3K9ac and H3K14ac. Interestingly, H3K14ac differences that persisted through transient hyperacetylation were supported by H3K4me3 differences, suggesting stabilization via cross talk. Conclusions: Quantitative variation of histone marks among S. cerevisiae strains is abundant and complex. Its relation to functional characteristics is modular and seems modest, with partial association with gene expression divergences, differences between functionally related marks and partial co-variation between marks that may confer stability. Thus, the specific context of studies, such as which precise marks, individuals and genomic loci are investigated, is primordial in population epigenomics studies. The complexity found in this pilot survey in yeast suggests that high complexity can be anticipated among higher eukaryotes, including humans. [ABSTRACT FROM AUTHOR]