Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Epigenetic dosage determines the major axis of β-cell heterogeneity and stratifies Type-1 and Type-2 β-cells [scRNA-seq]

ABSTRACT: Despite advances in single-cell technologies and the recent explosion in our understanding of cell-type heterogeneity, the mechanisms that specify and stabilize highly related cell subtypes remain poorly understood. Here, we demonstrate that the major axis of pancreatic β-cell heterogeneity is defined by dosage of the epigenetic silencing modification H3K27me3. We identify fundamentally distinct ‘Type-1’ and ‘Type-2’ β-cells that comprise ~95% of the β-cell compartment and that differ in their nuclear and cytosolic morphology, transcriptional output, and function. Type-1 β-cells exhibit higher global levels of H3K27me3, more compacted chromatin, and distinct chromatin organization. Both cell types are conserved in humans, and importantly, can be separated live by FACS sorting into CD24-positive (Type-1) and -negative (Type-2) β-cell fractions. Functionally, Type-1 cells exhibit increased mitochondrial mass, activity and insulin secretion both in vivo and ex vivo , and are enriched in human diabetes. Critically, loss of function studies in vivo indicate that precise H3K27me3 dosage is required to maintain β-cell heterogeneity and control proper Type-1 / Type-2 β-cell ratios in vivo. These data identify two novel and fundamentally distinct β-cell types, and demonstrate epigenetic dosage as a previously overlooked mechanism for establishing and maintaining cell-subtype specification and heterogeneity.

ORGANISM(S): Mus musculus

PROVIDER: GSE225436 | GEO | 2023/02/16

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Epigenetic dosage determines the major axis of β-cell heterogeneity and stratifies Type-1 and Type-2 β-cells [DNAmethArray]

Project description:Despite advances in single-cell technologies and the recent explosion in our understanding of cell-type heterogeneity, the mechanisms that specify and stabilize highly related cell subtypes remain poorly understood. Here, we demonstrate that the major axis of pancreatic β-cell heterogeneity is defined by dosage of the epigenetic silencing modification H3K27me3. We identify fundamentally distinct ‘Type-1’ and ‘Type-2’ β-cells that comprise ~95% of the β-cell compartment and that differ in their nuclear and cytosolic morphology, transcriptional output, and function. Type-1 β-cells exhibit higher global levels of H3K27me3, more compacted chromatin, and distinct chromatin organization. Both cell types are conserved in humans, and importantly, can be separated live by FACS sorting into CD24-positive (Type-1) and -negative (Type-2) β-cell fractions. Functionally, Type-1 cells exhibit increased mitochondrial mass, activity and insulin secretion both in vivo and ex vivo , and are enriched in human diabetes. Critically, loss of function studies in vivo indicate that precise H3K27me3 dosage is required to maintain β-cell heterogeneity and control proper Type-1 / Type-2 β-cell ratios in vivo. These data identify two novel and fundamentally distinct β-cell types, and demonstrate epigenetic dosage as a previously overlooked mechanism for establishing and maintaining cell-subtype specification and heterogeneity.

2023-02-16 | GSE224058 | GEO

Epigenetic dosage determines the major axis of β-cell heterogeneity and stratifies Type-1 and Type-2 β-cells [ChIP-seq]

2023-02-16 | GSE224060 | GEO

Epigenetic dosage determines the major axis of β-cell heterogeneity and stratifies Type-1 and Type-2 β-cells [RNA-seq]

2023-02-16 | GSE224059 | GEO

Single cell multi-omics analysis deconstructs diabetes-associated β-cell heterogeneity in human islets

Project description:The functional heterogeneity of β-cells is important for metabolism and diseases, but the nature and mechanism of such variation at molecular level remain elusive. Here we explore this question by comparing both single cell RNA-seq and single cell ATAC-seq maps of healthy and type II diabetic (T2D) human islets. We dissect the T2D-associated single cell trajectory and identified signature genes and enhancers in β-cells. We also map the 3D genome of both α- and β-cells with low-input eHi-C approach to unravel the cell type-specific gene regulatory circuits. Strikingly, more than one third of the T2D signature genes show significant intra-donor heterogeneity at single cell level; these genes are functionally distinct from other signature genes that are largely invariant among cells from the same individual but differentially expressed between donors, suggesting different roles in T2D pathogenesis. Importantly, we identified consistent intra-donor variations at both transcriptomic and epigenomic levels, which strongly support the heterogenous β-cell states and transcription programs. Finally, we construct the disease-signature regulatory networks and pinpointed HNF1A as one of the top transcription factors governing T2D-associated β-cell heterogeneity. Taken together, we provide the first multi-omic characterization of β-cell heterogeneity and reveals its connection to T2D.

2023-08-10 | GSE234754 | GEO

SC-beta Cell in vivo Maturation

Project description:SC-beta Cell in vivo Maturation

| PRJNA560712 | ENA

Single cell multi-omics analysis deconstructs diabetes-associated β-cell heterogeneity in human islets(scRNASeq)

2023-08-09 | GSE195986 | GEO

Single cell multi-omics analysis deconstructs diabetes-associated β-cell heterogeneity in human islets(scATACSeq)

2023-08-09 | GSE194401 | GEO

Single cell multi-omics analysis deconstructs diabetes-associated β-cell heterogeneity in human islets (Hi-C)

2023-08-09 | GSE195522 | GEO

Single cell transcriptome profiling of mouse pancreatic β-lineage cells and hESC-derived β-like cells

Project description:While pancreatic β cells have been shown to originate from endocrine progenitors in ductal regions, it remains unclear precisely where β cells emerge and which transcripts define newborn β cells. Here, we used a mouse model “Ins1-GFP;Timer” that provides spatial information during β-cell neogenesis with high temporal resolution. Fluorescent imaging demonstrated that, as expected, some newborn β cells arise close to the ducts; unexpectedly, all the others arise away from the ducts and adjacent to blood vessels. Single-cell RNA-sequencing (scRNA-seq) demonstrated five distinct populations of newborn β cells, confirming the spatial heterogeneity of β-cell neogenesis, and integration analysis with scRNA-seq of hESC-derived β-like cells uncovered transcriptional similarity with the data in mouse β cells. Thus, the combination of time-resolved histological imaging with single-cell transcriptional mapping demonstrated novel features of spatial and transcriptional heterogeneity in β-cell neogenesis, which will lead to a better understanding of β-cell differentiation for future cell therapy.

2022-03-04 | GSE155742 | GEO

Epigenomic plasticity enables human pancreatic alpha to beta cell reprogramming

Project description:Insulin-secreting β cells and glucagon-secreting α cells maintain physiological blood glucose levels, and their malfunction drives diabetes development. Using ChIP sequencing and RNA sequencing analysis, we determined the epigenetic and transcriptional landscape of human pancreatic α, β, and exocrine cells. We found that, compared with exocrine and β cells, differentiated α cells exhibited many more genes bivalently marked by the activating H3K4me3 and repressing H3K27me3 histone modifications. This was particularly true for β cell signature genes involved in transcriptional regulation. Remarkably, thousands of these genes were in a monovalent state in β cells, carrying only the activating or repressing mark. Our epigenomic findings suggested that α to β cell reprogramming could be promoted by manipulating the histone methylation signature of human pancreatic islets. Indeed, we show that treatment of cultured pancreatic islets with a histone methyltransferase inhibitor leads to colocalization of both glucagon and insulin and glucagon and insulin promoter factor 1 (PDX1) in human islets and colocalization of both glucagon and insulin in mouse islets. Thus, mammalian pancreatic islet cells display cell-type–specific epigenomic plasticity, suggesting that epigenomic manipulation could provide a path to cell reprogramming and novel cell replacement-based therapies for diabetes. Pancreatic islets were collected post-mortem from 6 human donors and subjected to FACS to separate populations of alpha, beta, and exocrine cells. Depending on the availability of resulting material, sorted islet cell populations were used for H3K4me3, H3K27me3 ChIP-seq, or RNA-seq analysis. All ChIP-seq samples have a corresponding input from the same sample.

2013-08-28 | E-GEOD-50386 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data