The CRTC-1 transcriptional domain is required for COMPASS complex-mediated longevity in C. elegans

作者：Carlos G. Silva-García, Laura I. Láscarez‐Lagunas, Katharina Papsdorf, Caroline Heintz, Aditi Prabhakar, Christopher S. Morrow, Lourdes Pajuelo Torres, Arpit Sharma, Jihe Liu, Mónica P. Colaiácovo, Anne Brunet, William B. Mair · 发表于：Nature Aging · 年份：2023 · DOI：10.1038/s43587-023-00517-8 · 被引用次数：13 · 研究领域：Genetics, Aging, and Longevity in Model Organisms、Histone Deacetylase Inhibitors Research、Epigenetics and DNA Methylation

Loss of function during aging is accompanied by transcriptional drift, altering gene expression and contributing to a variety of age-related diseases. CREB-regulated transcriptional coactivators (CRTCs) have emerged as key regulators of gene expression that might be targeted to promote longevity. Here we define the role of the Caenorhabditis elegans CRTC-1 in the epigenetic regulation of longevity. Endogenous CRTC-1 binds chromatin factors, including components of the COMPASS complex, which trimethylates lysine 4 on histone H3 (H3K4me3). CRISPR editing of endogenous CRTC-1 reveals that the CREB-binding domain in neurons is specifically required for H3K4me3-dependent longevity. However, this effect is independent of CREB but instead acts via the transcription factor AP-1. Strikingly, CRTC-1 also mediates global histone acetylation levels, and this acetylation is essential for H3K4me3-dependent longevity. Indeed, overexpression of an acetyltransferase enzyme is sufficient to promote longevity in wild-type worms. CRTCs, therefore, link energetics to longevity by critically fine-tuning histone acetylation and methylation to promote healthy aging.