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

• Published in: Nature aging Vol. 3; no. 11; pp. 1358 - 1371
• Main Authors: Silva-García, Carlos G, Láscarez-Lagunas, Laura I, Papsdorf, Katharina, Heintz, Caroline, Prabhakar, Aditi, Morrow, Christopher S, Pajuelo Torres, Lourdes, Sharma, Arpit, Liu, Jihe, Colaiácovo, Monica P, Brunet, Anne, Mair, William B
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.11.2023
• Subjects: Animals; Caenorhabditis elegans - genetics; Epigenesis, Genetic; Gene expression; Histones - chemistry; Longevity - genetics; Transcription Factors - genetics
• ISSN: 2662-8465; 2662-8465
• DOI: 10.1038/s43587-023-00517-8

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.