CRTC-1 Balances Histone Trimethylation and Acetylation to Promote Longevity

Silva-Garcia, C. G.; Lascarez-Lagunas, L. I.; Heintz, C.; Papsdorf, K.; Pajuelo, L.; Sharma, A.; Colaiacovo, M. P.; Brunet, A.; Mair, W. B.

doi:10.1101/2022.08.31.506037

bioRxiv · 10.1101/2022.08.31.506037

CRTC-1 Balances Histone Trimethylation and Acetylation to Promote Longevity

Silva-Garcia, C. G.·Lascarez-Lagunas, L. I.·Heintz, C.·Papsdorf, K.·Pajuelo, L.·Sharma, A.·Colaiacovo, M. P.·Brunet, A.·Mair, W. B.

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Abstract

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.

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Silva-Garcia, C. G., Lascarez-Lagunas, L. I., Heintz, C., Papsdorf, K., Pajuelo, L., Sharma, A., Colaiacovo, M. P., Brunet, A., Mair, W. B.. 2022-09-02. CRTC-1 Balances Histone Trimethylation and Acetylation to Promote Longevity. https://doi.org/10.1101/2022.08.31.506037

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