Silva-García, Carlos GiovanniHeintz, CarolinePrabhakar, AditiMorrow, Christopher S.Pajuelo Torres, LourdesSharma, ArpitLiu, JiheMair, William B.2023-12-142023-11-09Silva-García, Carlos Giovanni, Caroline Heintz, Aditi Prabhakar, Christopher S. Morrow, Lourdes Pajuelo Torres, Arpit Sharma, Jihe Liu et al. "The CRTC-1 transcriptional domain is required for COMPASS complex-mediated longevity in C. elegans." Nat Aging 3, no. 11 (2023): 1358-1371. DOI: 10.1038/s43587-023-00517-82662-8465https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37377520Loss of function during ageing 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 ageing.en-USNeuroscience (miscellaneous)Geriatrics and GerontologyAgingJournal Article2023-12-1410.1038/s43587-023-00517-8