Chromatin-associated YTHDC1 coordinates heat-induced reprograming of gene expression

Summary of the paper: Heat stress (HS) induces a cellular response leading to profound changes in gene expression. Here, we show that human YTHDC1, a reader of N6-methyladenosine (m6A) 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 m6A-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 m6A-dependent intron retention. Later, YTHDC1 concentrates within nuclear stress bodies (nSBs) where it binds to m6A-modified SATIII non-coding RNAs (ncRNAs), produced in a HSF1-dependent manner upon HS. These findings reveal that YTHDC1 plays a central role in a chromatin-associated m6A-based reprograming of gene expression during heat stress. Furthermore, they support the model where the temporary sequestration of YTHDC1 within nSBs subsequently calibrates the timing of this YTHDC1-dependent gene expression reprograming. Cell Reports 2022