Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes


  •    Defined open chromatin regions in sorted human α- and β-cells using ATAC-seq.
  •    Detected type 2 diabetes-associated risk loci in human α- and β-cell open chromatin.
  •    Classified human α- and β-cell-specific transcripts using mRNA-seq.
  •    Discovered novel human α- and β-cell signature proteins.
  •    Identified potential gene regulatory regions by integrating ATAC- and mRNA-seq data.

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. Researchers at the University of Pennsylvania set out to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. They 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.

The researchers 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.

They 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. They 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.

ATAC-seq results in sorted human α-, β-, and acinar cells.


(A) Experimental design. Islets from deceased organ donors were dispersed and FACS sorted into α-, β-, and acinar cell fractions, and processed for ATAC-seq analysis. N: nucleosome; T: transposase. Red and green bars represent PCR/sequencing barcodes. (B) Fragment lengths within a representative ATAC-seq library. The small fragments represent sequence reads in open chromatin, while the peak at ∼150 bp results from sequence reads that span one nucleosome, and larger peaks represent progressively more compact chromatin. (C) Heatmap of ATAC-seq peak data showing clustering of endocrine-selective peaks (present in α- and β-, but not acinar cells), α-cell-selective peaks, and β-cell-selective peaks. Inter-sample correlation is noted at the bottom. (D) Number of peaks identified by ATAC-seq in each cell type that are specific to that cell type versus also found in either of the other two cell types investigated. (E) Venn diagram of overlap of α-cell-selective and β-cell-selective ATAC-seq peaks, after removal of peaks also found in acinar cells.

Ackermann AM, Wang Z, Schug J, Naji A, Kaestner KH. (2016) Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes. Molecular Metabolism [Epub ahead of print]. [article]

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