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H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Drosophila melanogaster

PROVIDER: GSE181951 | GEO | 2022/08/11

REPOSITORIES: GEO

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H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [RNA-seq]

Project description:Insufficient insulin release by β-cells is the primary etiology in type 2 diabetes (T2D) and coincides with impaired expression of genes essential to β-cell function, but drivers of gene expression dysregulation are not well resolved. We find that H3K4me3 peak breadth correlates with gene expression dysregulation in T2D. Using an adult β-cell Dpy30-KO mouse model, we show that global reduction of H3K4 methylation causes downregulation of genes also downregulated in T2D. Reduction of H3K4 methylation increases transcriptional entropy and reduces insulin production and glucose-responsiveness. Depletion of H3K4 methylation causes global dilution of epigenetic complexity but does not generally reduce gene expression – instead, genes related to β-cell function and/or in particular chromatin environments are specifically affected. Our data further suggests that promoter-associated H3K4me1 is sufficient to maintain expression in the absence of H3K4me3. These data implicate dysregulation of H3K4 methylation in destabilizing gene expression and contributing to β-cell dysfunction in T2D.

2022-08-11 | GSE181950 | GEO

H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [ChIP-seq]

2022-08-11 | GSE181949 | GEO

H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes.

Project description:H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes.

| PRJNA754029 | ENA

H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [RNA-seq]

Project description:H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [RNA-seq]

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H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [ChIP-seq]

Project description:H3K4 Methylation in β-cells prevents transcriptional downregulation and variance associated with type 2 diabetes [ChIP-seq]

| PRJNA754033 | ENA

Beta Cell Dedifferentiation Induced by IRE1α Deletion Prevents Type 1 Diabetes.

Project description:Immune-mediated destruction of insulin-producing β cells causes type 1 diabetes (T1D). However, how β cells participate in their own destruction during the disease process is poorly understood. Here, we report that modulating the unfolded protein response (UPR) in β cells of non-obese diabetic (NOD) mice by deleting the UPR sensor IRE1α prior to insulitis induced a transient dedifferentiation of β cells, resulting in substantially reduced islet immune cell infiltration and β cell apoptosis. Single-cell and whole-islet transcriptomics analyses of immature β cells revealed remarkably diminished expression of β cell autoantigens and MHC class I components, and upregulation of immune inhibitory markers. IRE1α-deficient mice exhibited significantly fewer cytotoxic CD8+ T cells in their pancreata, and adoptive transfer of their total T cells did not induce diabetes in Rag1-/- mice. Our results indicate that inducing β cell dedifferentiation, prior to insulitis, allows these cells to escape immune-mediated destruction and may be used as a novel preventive strategy for T1D in high-risk individuals.

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Targeted elimination of senescent beta cells prevents Type 1 Diabetes

Project description:scRNA-seq of Islets isolated from 8, 14 and 16 week NOD mice

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Altered nucleosome occupancy and histone H3K4 methylation in response to 'transcriptional stress'.

Project description:We report that under 'transcriptional stress' in budding yeast, when most pol II activity is acutely inhibited, rapid deposition of nucleosomes occurs within genes, particularly at 3' positions. Whereas histone H3K4 trimethylation normally marks 5' ends of highly transcribed genes, under 'transcriptional stress' induced by 6-azauracil (6-AU) and inactivation of pol II, TFIIE or CTD kinases Kin28 and Ctk1, this mark shifted to the 3' end of the TEF1 gene. H3K4Me3 at 3' positions was dynamic and could be rapidly removed when transcription recovered. Set1 and Chd1 are required for H3K4 trimethylation at 3' positions when transcription is inhibited by 6-AU. Furthermore, Deltachd1 suppressed the growth defect of Deltaset1. We suggest that a 'transcriptional stress' signal sensed through Set1, Chd1, and possibly other factors, causes H3K4 hypermethylation of newly deposited nucleosomes at downstream positions within a gene. This response identifies a new role for H3K4 trimethylation at the 3' end of the gene, as a chromatin mark associated with impaired pol II transcription.

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Enhancer-associated H3K4 methylation safeguards in vitro germline competence.

Project description:Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.

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Early senescence-induced immunosuppressive β-cell secretome prevents type 1 diabetes

Project description:During the progression of type 1 diabetes (T1D), β-cells are exposed to significant stress and therefore require adaptive responses to survive. The adaptive mechanisms that can preserve β-cell function and survival in the face of autoimmunity remain unclear. Here we show that deletion of the unfolded protein response genes, Atf6α or Ire1α, in β-cells of NOD mice prior to insulitis generates a p21-driven early senescence phenotype and altered β-cell secretome that significantly enhances leukemia inhibitory factor-mediated recruitment of M2 macrophages to the islets. Consequently, M2 macrophages promote anti-inflammatory responses and immune surveillance that cause resolution of islet inflammation, removal of terminally senesced β-cells, reduction of β-cell apoptosis, and prevention of T1D. We further demonstrate that p21-mediated early senescence signature is conserved in residual β-cells of T1D patients. Our findings reveal a previously unrecognized link between β-cell UPR and senescence that, if leveraged, may represent a novel therapeutic strategy for T1D.

2023-11-20 | GSE239947 | GEO

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