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

Loss 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. set-2 mutants [set-2] are long-lived due to changes in epigenetic modifications. CRTC-1 is required to promote this longevity phenotype since the double mutants set-2;crtc-1(CBD) [WBMB1036] show a normal lifespan. CRTC-1 regulates this set-2-dependent longevity through its CBD domain, which is important to modulate transcription. In order to identify the CRTC-1(CBD)-dependent transcriptional changes in the set-2 mutants, we performed an RNA-seq analysis in the following strains wild type [N2], set-2 [set-2], crtc-1(CBD) [WBM1041], and se-2;crtc-1(CBD) [WBM1036].