OBJECTIVE: Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity.
METHODS: We sorted human α- and β-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions.
RESULTS: We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in β-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes.
CONCLUSIONS: We have determined the genetic landscape of human α- and β-cells based on chromatin accessibility and transcript levels, which allowed for detection of novel α- and β-cell signature genes not previously known to be expressed in islets. Using fine-mapping of open chromatin, we have identified thousands of potential cis-regulatory elements that operate in an endocrine cell type-specific fashion.

[Untagged]
━ Inclusion
━ ━ 1,3-butadiene
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ 4-Aminobiphenyl
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ Histone modification
━ ━ Aflatoxins
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ Benzene
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Rat
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Benzidine
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Benzo[a]pyrene
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ lncRNA
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Coke production
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ ━ DNA methylation
━ ━ Formaldehyde
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ Histone modification
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Rat
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Other
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ Histone modification
━ ━ MOCA
━ ━ ━ Rat
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ Histone modification
━ ━ Occupational exposure as a painter
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ ━ Sulfur Mustard
━ ━ ━ Human
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ DNA methylation
━ ━ ━ ━ ━ microRNA
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ microRNA
━ ━ ━ Mouse
━ ━ ━ ━ in vitro
━ ━ ━ ━ ━ microRNA
━ ━ Vinyl chloride
━ ━ ━ Human
━ ━ ━ ━ in vivo
━ ━ ━ ━ ━ DNA methylation
━ Exclusion
━ ━ no epigenetics
━ ━ ━ y-H2AX
━ ━ ━ histone-carcinogen binding
━ ━ not chemical of interest
━ ━ cannot access full text
━ ━ review or comment
━ ━ other
━ ━ ━ carcinogen binding to (existant) methylated cytosines
━ ━ ━ caricinogen binding and (existant) chromatin structure

References (1685 found)

HAWC