Sustained activation of AMPK enhances differentiation of human iPSC-derived cardiomyocytes via sirtuin activation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE152265 | GEO | 2020/06/12
REPOSITORIES: GEO
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Project description:Sustained activation of AMPK enhances differentiation of human iPSC-derived cardiomyocytes via sirtuin activation
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on disease for the two sexes have been noted, underlying reasons are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences and find that Sirt7-/- females have decreased fitness throughout the lifespan. Intriguingly, SIRT7 preferentially localizes to the sex chromosomes. In females, SIRT7 loss affects “X-chromosome inactivation” (XCI), the 1st arm of dosage compensation that equalizes X-linked gene expression between males and females. Xist is overexpressed and gene silencing becomes more efficient. Surprisingly, however, SIRT7 loss has greatest impact on the active X (Xa). The Xa becomes hyperacetylated on H3K36ac, structurally disorganized, prone to DNA damage, and overexpressed. Increased Xa expression leads to genome imbalance and augmented “X-chromosome upregulation” (XCU) — the 2nd arm of dosage compensation that balances X-chromosome versus autosomal gene expression. These data reveal an essential crosstalk between sirtuins and the sex chromosomes, with SIRT7 safeguarding X-chromosome integrity and dosage balance with autosomes. We propose that the sex bias in Sirtuin 7 biology can be explained in part by unequal effects on the sex chromosomes. This SuperSeries is composed of the SubSeries listed below.
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Project description:Sir2 and the homologous proteins, Hst1, Hst2, Hst3, and Hst4 from Saccharomyces cerevisiae are NAD+-dependent histone deacetylases of the sirtuin protein family. Sir2 functions in transcriptional silencing at the silent mating-type loci, telomeres, and rDNA locus, but also promotes replicative lifespan. To gain a better understanding of the chromatin-regulatory roles carried out by Sir2 and the Hst proteins, we performed ChIP-sequencing analysis on all five sirtuins and Sum1, the DNA binding partner for Hst1. Sir2, Hst1, and Sum1 were abundantly, and functionally co-enriched at several major targets, including the telomeric repeats, where they were required for maintaining proper telomere repeat length. At tRNA target genes they were required for efficient cohesin and condensin deposition. Across the open reading frames of glycolytic and ribosomal protein genes, Sir2 and Hst1 functioned in NAD+-dependent transcriptional repression at the diauxic shift, directly linking Sir2 to glucose metabolism, which could have implications for longevity. Six factors and Input ChIP-seq samples were analyzed in Saccharomyces eerevisiae.
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Project description:Sirtuins are NAD+-dependent deacylases with diverse enzymatic activities and substrates. They were implicated in regulation of cancer progression, neurodegeneration, aging, and viral infection. Sirtuin-2 localizes to the cytoplasm and is known to deacetylate alpha-tubulin. Current knowledge on sirtuin-2 interactions and its effect on gene expression in normal cells is very limited. We used proteomics approach to define its interactions and its effect on global protein levels in human fibroblasts.
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Project description:Expression profiling, ChiP-CHIP and phenotypic analysis were used to investigate the functional relationships of class III NAD+-dependent HDACs (Sirtuins) in fission yeast. We detected significant histone acetylation increases in Sirtuin mutants at their specific genomic binding targets and were thus able to identify an in vivo substrate preference for each Sirtuin. At heterochromatic loci, we demonstrate that although Hst2 is mainly cytoplasmic, a nuclear pool of Hst2 co-localises with the other Sirtuins at silent regions (cen, mat, tel, rDNA) and that like the other Sirtuins, Hst2 is required for rDNA and centromeric silencing. Interestingly we found specific functions for the fission yeast Sirtuins Hst2 and Hst4 in gene regulation. Hst2 directly represses genes involved in transport and membrane function whereas Hst4 represses amino acid biosynthesis genes and Tf2 retrotransposons. A specific role for Hst4 in Tf2 5’ mRNA processing was revealed. Thus, Sirtuins share functions at many genomic targets, but Hst2 and Hst4 have also evolved unique functions in gene regulation. Keywords: chromatin; fission yeast; gene silencing; retrotransposon; Sirtuin; HDAC
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on the two sexes has been noted, underlying causes for sex biases in aging and cancer are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences. We find that Sirt7-/- females have decreased fitness during embryogenesis and throughout life. Intriguingly, SIRT7 preferentially localizes to the X-chromosome, suggesting a potential defect in X-inactivation — the arm of dosage compensation that equalizes X-chromosome expression between XX females and XY males. Indeed, SIRT7 ablation causes increased Xist RNA levels, H3K27me3 enrichment, and gene repression on the inactive X (Xi) chromosome. Surprisingly, however, loss of SIRT7 exerts greatest effects on the active X (Xa). In Sirt7-/- females, the Xa demonstrates 3D structural disorganization, increased chromatin mixing, and acute propensity to break and form chromosome fusions in an Xa-specific manner. Disproportional to autosomes and Xi, the Xa becomes super-acetylated on H3K36 and super-activated in gene expression, resulting in an imbalance in the 2nd arm of dosage compensation — known as “Xa-hyperactivation” — which evolved to balance X-linked gene expression against the genome. These data reveal a crosstalk between sirtuins and dosage compensation and identify a novel regulator of Xa-hyperactivation.
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on the two sexes has been noted, underlying causes for sex biases in aging and cancer are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences. We find that Sirt7-/- females have decreased fitness during embryogenesis and throughout life. Intriguingly, SIRT7 preferentially localizes to the X-chromosome, suggesting a potential defect in X-inactivation — the arm of dosage compensation that equalizes X-chromosome expression between XX females and XY males. Indeed, SIRT7 ablation causes increased Xist RNA levels, H3K27me3 enrichment, and gene repression on the inactive X (Xi) chromosome. Surprisingly, however, loss of SIRT7 exerts greatest effects on the active X (Xa). In Sirt7-/- females, the Xa demonstrates 3D structural disorganization, increased chromatin mixing, and acute propensity to break and form chromosome fusions in an Xa-specific manner. Disproportional to autosomes and Xi, the Xa becomes super-acetylated on H3K36 and super-activated in gene expression, resulting in an imbalance in the 2nd arm of dosage compensation — known as “Xa-hyperactivation” — which evolved to balance X-linked gene expression against the genome. These data reveal a crosstalk between sirtuins and dosage compensation and identify a novel regulator of Xa-hyperactivation.
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on the two sexes has been noted, underlying causes for sex biases in aging and cancer are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences. We find that Sirt7-/- females have decreased fitness during embryogenesis and throughout life. Intriguingly, SIRT7 preferentially localizes to the X-chromosome, suggesting a potential defect in X-inactivation — the arm of dosage compensation that equalizes X-chromosome expression between XX females and XY males. Indeed, SIRT7 ablation causes increased Xist RNA levels, H3K27me3 enrichment, and gene repression on the inactive X (Xi) chromosome. Surprisingly, however, loss of SIRT7 exerts greatest effects on the active X (Xa). In Sirt7-/- females, the Xa demonstrates 3D structural disorganization, increased chromatin mixing, and acute propensity to break and form chromosome fusions in an Xa-specific manner. Disproportional to autosomes and Xi, the Xa becomes super-acetylated on H3K36 and super-activated in gene expression, resulting in an imbalance in the 2nd arm of dosage compensation — known as “Xa-hyperactivation” — which evolved to balance X-linked gene expression against the genome. These data reveal a crosstalk between sirtuins and dosage compensation and identify a novel regulator of Xa-hyperactivation.
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on the two sexes has been noted, underlying causes for sex biases in aging and cancer are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences. We find that Sirt7-/- females have decreased fitness during embryogenesis and throughout life. Intriguingly, SIRT7 preferentially localizes to the X-chromosome, suggesting a potential defect in X-inactivation — the arm of dosage compensation that equalizes X-chromosome expression between XX females and XY males. Indeed, SIRT7 ablation causes increased Xist RNA levels, H3K27me3 enrichment, and gene repression on the inactive X (Xi) chromosome. Surprisingly, however, loss of SIRT7 exerts greatest effects on the active X (Xa). In Sirt7-/- females, the Xa demonstrates 3D structural disorganization, increased chromatin mixing, and acute propensity to break and form chromosome fusions in an Xa-specific manner. Disproportional to autosomes and Xi, the Xa becomes super-acetylated on H3K36 and super-activated in gene expression, resulting in an imbalance in the 2nd arm of dosage compensation — known as “Xa-hyperactivation” — which evolved to balance X-linked gene expression against the genome. These data reveal a crosstalk between sirtuins and dosage compensation and identify a novel regulator of Xa-hyperactivation.
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Project description:Sirtuins are deacetylases implicated in stress responses and longevity in mammals. Although their differential impact on the two sexes has been noted, underlying causes for sex biases in aging and cancer are not known. Here, using Sirtuin 7 (SIRT7) as a model in mice, we probe mechanisms leading to sex differences. We find that Sirt7-/- females have decreased fitness during embryogenesis and throughout life. Intriguingly, SIRT7 preferentially localizes to the X-chromosome, suggesting a potential defect in X-inactivation — the arm of dosage compensation that equalizes X-chromosome expression between XX females and XY males. Indeed, SIRT7 ablation causes increased Xist RNA levels, H3K27me3 enrichment, and gene repression on the inactive X (Xi) chromosome. Surprisingly, however, loss of SIRT7 exerts greatest effects on the active X (Xa). In Sirt7-/- females, the Xa demonstrates 3D structural disorganization, increased chromatin mixing, and acute propensity to break and form chromosome fusions in an Xa-specific manner. Disproportional to autosomes and Xi, the Xa becomes super-acetylated on H3K36 and super-activated in gene expression, resulting in an imbalance in the 2nd arm of dosage compensation — known as “Xa-hyperactivation” — which evolved to balance X-linked gene expression against the genome. These data reveal a crosstalk between sirtuins and dosage compensation and identify a novel regulator of Xa-hyperactivation.
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