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

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.

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: William B. Mair

PROVIDER: PXD045674 | JPOST Repository | Tue Sep 26 00:00:00 BST 2023

REPOSITORIES: jPOST

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

Project description: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.

2023-09-28 | PXD045747 | JPOST Repository

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

2023-08-02 | GSE239572 | GEO

An apicomplexan bromodomain, TgBDP1 associates with diverse epigenetic factors to regulate essential transcriptional processes in Toxoplasma gondii.

Project description:The protozoan pathogen Toxoplasma gondii relies on tight regulation of gene expression to invade and establish infection in its host. The divergent gene regulatory mechanisms of Toxoplasma and related apicomplexan pathogens rely heavily on regulators of chromatin structure and histone modifications. The important contribution of histone acetylation for Toxoplasma in both acute and chronic infection has been demonstrated, where histone acetylation increases at active gene loci. However, the direct consequences of specific histone acetylation marks and the signaling pathway that influences transcriptional regulation in response to the modification is unclear. As a reader of lysine acetylation, the bromodomain serves as a mediator between the acetylated histone and transcriptional regulators. Here we show that the bromodomain protein TgBDP1 which is conserved amongst Apicomplexa and within the Alveolata superphylum, is essential for Toxoplasma asexual proliferation. Using CUT&TAG we demonstrate that TgBDP1 is recruited to transcriptional start sites of a large proportion of parasite genes. Transcriptional profiling during TgBDP1 knockdown revealed that loss of TgBDP1 leads to major dysregulation of gene expression, implying multiple roles for TgBDP1 in both gene activation and repression. This is supported by interactome analysis of TgBDP1 demonstrating that TgBDP1 forms a core complex with two other bromodomain proteins and an ApiAP2 factor. This core complex appears to interact with other epigenetic factors such as nucleosome remodelling complexes. We conclude that TgBDP1 interacts with diverse epigenetic regulators to exert opposing influences on gene expression in the Toxoplasma tachyzoite.

2023-06-01 | PXD038848 | Pride

Gene Expression Analysis of Fat Body of Drosophila melanogaster Subjected to Sir2 Overexpression or Dietary Restriction

Project description:Sir2 is the most intensively discussed longevity gene in current aging research. Although the gene encoding for a NAD+-dependent histone deacetylase initially was found to extend lifespan of various organisms ranging from yeast to mammals, serious doubts regarding its role in longevity have been expressed recently. In this study, we tested whether tissue-specific overexpression of Sir2 in the adult fat body can extend lifespan when compared to genetically identical controls. We also wanted to elucidate the mechanisms by which fat body Sir2 promotes longevity by studying the phenotypic and transcriptional changes in the fat body. We found that moderate (3-fold) Sir2 overexpression in the fat body during adulthood only can promote longevity in both sexes by roughly 13 %. In addition, we obtained transcriptional profiles elicited by this overexpression and propose a role for Sir2 in lipid droplet biology especially under conditions of starvation. Furthermore, our data do not support the idea of Sir2 mediating the response to dietary restriction (DR) because transcriptional profiles of fat bodies after DR or Sir2 overexpression do not match. This study provides additional independent evidence for the concept of Sir2 as a longevity gene and as a promising pharmacological target to cure age-related diseases. 6 groups of sample types were included in the experiment: a) females overexpressing Sir2 in the fat body b) female controls c) males overexpressing Sir2 in the fat body d) male controls e) wildtype females subjected to DR f) wildtype females feeding on a normal diet. 3 biological replicates were included per group.

2013-05-01 | E-GEOD-45974 | biostudies-arrayexpress

NHR-49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

Project description:Endogenous and exogenous stresses elicit transcriptional responses that limit damage and promote cell/organismal survival. Like its mammalian counterparts, Hepatocyte Nuclear Factor 4 (HNF4) and peroxisome proliferator-activated receptor a (PPARa), Caenorhabditis elegans NHR-49 is a well-established regulator of lipid metabolism. Here, we reveal that NHR-49 is essential to activate a transcriptional response common to organic peroxide and fasting, which includes the pro-longevity gene fmo-2/flavin-containing monoxygenase. These NHR-49-dependent, stress-responsive genes are also upregulated in long-lived glp-1/notch receptor mutants, and two of them contribute to increased oxidative stress resistance in wild-type worms and long-lived glp-1 mutants. Similar to its role in lipid metabolism, NHR-49 requires the Mediator subunit mdt-15 to promote stress-induced gene expression. However, NHR-49 acts independently from the transcription factor hlh-30/TFEB that also promotes fmo-2 expression. Similarly, activation of the p38 MAPK, PMK-1, which is important for adaptation to a variety of stresses, is only important for peroxide-induced expression of a subset of NHR-49-dependent genes, including fmo-2. Notably, we find that organic peroxide increases NHR-49 protein levels, apparently by a post-transcriptional mechanism that does not require PMK-1 activation. Together these findings establish a new role for the HNF4/PPARa-related NHR-49 as a stress-activated regulator of cytoprotective gene expression.

2018-03-05 | GSE107799 | GEO

Histone deacetylase inhibitors cause the selective depletion of bromodomain containing proteins

Project description:Histone deacetylases (HDACs) and acetyltransferases control the epigenetic regulation of gene expression through modification of histone marks. Histone deacetylase inhibitors (HDACi) are small molecules that interfere with histone tail modification thus altering chromatin structure and epigenetically controlled pathways. They promote apoptosis in proliferating cells and are promising anti-cancer drugs. While some HDACis have already been approved for therapy and others are in different phases of clinical trials, the exact mechanism of action of this drug class remains elusive. Previous studies have shown that HDACis cause massive changes in chromatin structure but only moderate changes in gene expression. To which extent these changes manifest at the protein level has never been investigated on a proteome-wide scale. Here, we have studied HDACi-treated cells by large-scale mass spectrometry based proteomics. We show that HDACi treatment affects primarily the nuclear proteome and induces a selective decrease of bromodomain containing proteins (BCPs), the main readers of acetylated histone marks. By combining time-resolved proteome and transcriptome profiling, we show that BCPs are affected at the protein level as early as 12 hours after HDACi treatment and that their abundance is regulated by a combination of transcriptional and post-transcriptional mechanisms. Using gene silencing, we demonstrate that the decreased abundance of BCPs is sufficient to mediate important transcriptional changes induced by HDACi. Our data reveals a new aspect of the mechanism of action of HDACi that is mediated by an interplay between histone acetylation and the abundance of BCPs.

2015-03-18 | PXD001660 | Pride

G9a-Mediated Methylation of ERα Links the PHF20/MOF Histone Acetyltransferase Complex to Hormonal Gene Expression

Project description:The euchromatin histone methyltransferase 2 (EHMT2, aka G9a) methylates histone H3K9 to repress gene expression, but it also acts as a coactivator for some nuclear receptors. The molecular mechanisms underlying this activation remain elusive. Here we show that G9a functions as a bona fide coactivator of the endogenous estrogen receptor α (ERα) in breast cancer cells in a histone methylation-independent manner. G9a dimethylates ERα protein at lysine 235 both in vitro and in cells. Dimethylation of ERαK235 (ERαK235me2) is recognized by the Tudor domain of PHF20, which in turn recruits the MOF histone acetyltransferase (HAT) complex to ERα target gene promoters to deposit histone H4K16 acetylation promoting active transcription. Together, our in vitro and in vivo data establish the molecular mechanism by which G9a functions as an ERα coactivator. Along with the PHF20/MOF complex, G9a links the crosstalk between ERα methylation and histone acetylation governing the epigenetic regulation of hormonal gene expression.

2016-04-07 | GSE76507 | GEO

Gcn4-dependent translation reduction in long-lived ribosomal protein deletion strains

Project description:Deletion of several ribosomal proteins genes (RPKOs) has been shown to extend the lifespan of Saccharomyces cerevisiae in a Gcn4-dependent manner. To characterize the underlying mechanisms, we systematically analyzed the gene expression of both short- and long-lived RPKO strains at multiple levels. We found that up-regulation of amino acid biosynthesis and global down-regulation of protein synthesis are hallmarks of long-lived strains. We provide direct evidence that gene expression changes observed in long-lived strains result from translational up-regulation of GCN4 mRNA via skipping of upstream open reading frames (uORFs), in turn due to slow/defective ribosome assembly. We further demonstrate that Gcn4 acts as a transcriptional repressor on promoters of translation-related genes, thereby globally reducing protein synthesis. Our data suggest that the Gcn4-dependent increase in lifespan can be attributed partially to its ability to dampen the translation capacity of the cell, thereby engaging a well known mechanism of longevity.

2017-07-06 | PXD004760 | Pride

Gene Expression Analysis of Fat Body of Drosophila melanogaster Subjected to Sir2 Overexpression or Dietary Restriction

2013-05-01 | GSE45974 | GEO

Lipids reprogram cellular metabolism to become a major carbon source for histone acetylation.

Project description:From McDonnell et. al. Cell Reports 2016: Cells integrate nutrient sensing and metabolism to coordinate proper cellular responses to a particular nutrient source. For example, glucose drives a gene expression program characterized by activating genes involved in its metabolism, in part, by increasing glucose-derived histone acetylation. Here, we find that lipid-derived acetyl-CoA is a major source of carbon for histone acetylation. Using 13C-carbon tracing combined with acetyl-proteomics, we show that up to 90% of acetylation on certain histone lysines can be derived from fatty acid carbon, even in the presence of excess glucose. By repressing both glucose and glutamine metabolism, fatty acid oxidation reprograms cellular metabolism leading to increased lipid-derived acetyl-CoA. Gene expression profiling of octanoate-treated hepatocytes shows a pattern of upregulated lipid metabolic genes, demonstrating a specific transcriptional response to lipid. These studies expand the landscape of nutrient sensing and uncover how lipids and metabolism are integrated by epigenetic events that control gene expression.

2016-12-22 | PXD005040 | Pride

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