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

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. He...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10645585/
https://www.ncbi.nlm.nih.gov/pubmed/37946042
http://dx.doi.org/10.1038/s43587-023-00517-8
Descripción
Sumario: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.