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Chromatin reorganization drives expression of functional maturation genes in senescent pancreatic beta cells (Series4- chromatin profiles, MINT-ChIP)

ABSTRACT: Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207825 | GEO | 2024/06/26

REPOSITORIES: GEO

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Chromatin reorganization drives expression of functional maturation genes in senescent pancreatic beta cells (Series2 - chromatin sccessibility, ATAC-seq)

Project description:Using a unique model of cultured human beta cell senescence we show that chromatin reorganization leads to activation of enhancers regulating functional maturation genes, concomitantly with acquisition of glucose-stimulated insulin secretion capacity. Interferon-response genes are elevated in senescent beta cells, but cytokine-encoding senescence-associated secretory phenotype (SASP) genes are not. Human beta cell senescence thus involves chromatin-driven upregulation of a functional maturation program and of interferon-stimulated genes, changes that could increase both insulin secretion and immune reactivity.

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SC-beta Cell in vivo Maturation

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Acceleration of beta cell aging plays a key role in diabetes and senolysis improves metabolic, functional and cellular outcomes

Project description:The risk of type 2 diabetes increases with age. Although changes in function and proliferation of aged beta cells resemble those preceding the development of diabetes, the contribution of beta cell aging and senescence remains unclear. The proportion of aged beta cells increases with animal age but even in young mice, senescent beta cells can be found. We showed that different models of insulin resistance accelerated aging and senescence marker expression in beta cells, BGal, led to loss of function and impaired glucose tolerance. Clearance of p16Ink4a+ cells, using the INK-ATTAC mouse model, ameliorated glucose metabolism, insulin secretion and decreased expression of aging, senescence and SASP genes in pancreatic islets. Senolytic drug ABT263 also improved glucose metabolism and beta cell identity when administered during insulin resistance. Human beta cells from diabetic and non-diabetic donors shared some of the same biology laying the foundation for translation into humans. These novel findings lay the framework to pursue senolysis of beta cells as a preventive and alleviating strategy for T2D.

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Unique human beta-cell senescence-associated secretory phenotype (SASP) reveal conserved signaling pathways and heterogeneous factors

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Project description:Senescent cells release a variety of cytokines, proteases and growth factors collectively defined as the Senescent Secretory Associated Phenotype (SASP). Sustained SASP induces a pattern of chronic inflammation associated with aging and implicated in multiple age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP factor, in multiple senescence models. First, we characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We identified IRF1 (interferon response factor 1) as a transcription factor required for promoting BAFF mRNA transcription in senescence, and found that suppressing BAFF production decreased the senescent phenotype in both monocytes and fibroblasts. Importantly, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-κB and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). Overall, BAFF silencing affected shared senescence-associated phenotypes including IL6 secretion, SA-beta-Gal staining, and γ-H2AX accumulation. We propose that BAFF is a novel biomarker of senescence and a potential target for senotherapy.

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TEAD4 delays cellular senescence by remodeling chromatin accessibility at H3K27ac-occupied enhancer regions [RNA-seq]

Project description:Dramatic alterations in epigenetic landscapes are known to affect genome accessibility and their transcriptional program. Extensive evidences have emerged that senescent cells accumulate profound chromatin tremendous reordering upon senescence entry, yet, the underlying mechanisms between epigenetic parameters and gene expression profile have not been fully clarified. In this report, we delineate the genome-wide redistribution of accessible chromatin regions leading to broad transcriptome effects during UC-MSCs senescence. We report the distinct senescence-activated accessibility regions (SAAs) are always distributed in H3K27ac decorated enhancer regions, where the SAAs are responsible for elevated flanking SASP expression and aberrant cellular signaling relevant to SASP secretion. Mechanistically, a single transcription factor, TEAD4, shifting away from H3K27ac-labled SAAs and leading to prominent chromatin accessibility reconstruction during senescence. The enhanced signal of SAAs driven by TEAD4 suppression subsequently induce a robust decrease of adjacent SASP genes expression and downstream factors secretion, and finally, contributing to the progression of senescence. Our findings illustrate a dynamic landscape of chromatin accessibility following senescence entry and reveal an insightful function for TEAD4 in regulating the broad chromatin state that modulate the overall transcriptional program of the SASP genes.

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