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Heintz, Caroline

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Heintz

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Caroline

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Heintz, Caroline
Author's Publications: search.filters.isAuthorOfPublication.3310453f-36fe-4922-851e-e47d003bdc00

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    Splicing factor 1 modulates dietary restriction and TORC1 pathway longevity in C. elegans
    (Springer Nature, 2016) Heintz, Caroline; Doktor, Thomas K.; Lanjuin, Anne; Escoubas, Caroline; Zhang, Yue; Weir, Heather; Dutta, Sneha; Silva-García, Carlos Giovanni; Bruun, Gitte H.; Morantte, Ianessa; Hoxhaj, Gerta; Manning, Brendan; Andresen, Brage S.; Mair, William
    Ageing is driven by a loss of transcriptional and protein homeostasis1, 2, 3 and is the key risk factor for multiple chronic diseases. Interventions that attenuate or reverse systemic dysfunction associated with age therefore have the potential to reduce overall disease risk in the elderly. Precursor mRNA (pre-mRNA) splicing is a fundamental link between gene expression and the proteome, and deregulation of the splicing machinery is linked to several age-related chronic illnesses4, 5. However, the role of splicing homeostasis in healthy ageing remains unclear. Here we demonstrate that pre-mRNA splicing homeostasis is a biomarker and predictor of life expectancy in Caenorhabditis elegans. Using transcriptomics and in-depth splicing analysis in young and old animals fed ad libitum or subjected to dietary restriction, we find defects in global pre-mRNA splicing with age that are reduced by dietary restriction via splicing factor 1 (SFA-1; the C. elegans homologue of SF1, also known as branchpoint binding protein, BBP). We show that SFA-1 is specifically required for lifespan extension by dietary restriction and by modulation of the TORC1 pathway components AMPK, RAGA-1 and RSKS-1/S6 kinase. We also demonstrate that overexpression of SFA-1 is sufficient to extend lifespan. Together, these data demonstrate a role for RNA splicing homeostasis in dietary restriction longevity and suggest that modulation of specific spliceosome components may prolong healthy ageing.
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    The CRTC-1 transcriptional domain is required for COMPASS complex-mediated longevity in C. elegans
    (Springer Science and Business Media LLC, 2023-11-09) Silva-García, Carlos Giovanni; Heintz, Caroline; Prabhakar, Aditi; Morrow, Christopher S.; Pajuelo Torres, Lourdes; Sharma, Arpit; Liu, Jihe; Mair, William B.
    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.