A heat shock-responsive lncRNA <i>Heat</i> acts as a HSF1-directed transcriptional brake via m⁶A modification.

Abstract

Long noncoding RNAs (lncRNAs) are key regulators of gene expression in diverse cellular contexts and biological processes. Given the surprising range of shapes and sizes, how distinct lncRNAs achieve functional specificity remains incompletely understood. Here, we identified a heat shock-inducible lncRNA, <i>Heat</i>, in mouse cells that acts as a transcriptional brake to restrain stress gene expression. Functional characterization reveals that <i>Heat</i> directly binds to heat shock transcription factor 1 (HSF1), thereby targeting stress genes in a trans-acting manner. Intriguingly, <i>Heat</i> is heavily methylated in the form of m⁶A. Although dispensable for HSF1 binding, <i>Heat</i> methylation is required for silencing stress genes to attenuate heat shock response. Consistently, m⁶A depletion results in prolonged activation of stress genes. Furthermore, <i>Heat</i> mediates these effects via the nuclear m⁶A reader YTHDC1, forming a transcriptional silencing complex for stress genes. Our study reveals a crucial role of nuclear epitranscriptome in the transcriptional regulation of heat shock response.