Abstract
Alpha TC1 (αTC1) and Beta-TC-6 (βTC6) mouse islet cell lines are cellular models of islet (dys)function and type 2 diabetes (T2D). However, genomic characteristics of these cells, and their similarities to primary islet alpha and beta cells, are undefined. Here, we report the epigenomic (ATAC-seq) and transcriptomic (RNA-seq) landscapes of αTC1 and βTC6 cells. Each cell type exhibits hallmarks of its primary islet cell counterpart including cell-specific expression of beta (e.g., Pdx1) and alpha (e.g., Arx) cell transcription factors (TFs), and enrichment of binding motifs for these TFs in αTC1/βTC6 cis-regulatory elements. αTC1/βTC6 transcriptomes overlap significantly with the transcriptomes of primary mouse/human alpha and beta cells. Our data further indicate that ATAC-seq detects cell-specific regulatory elements for cell types comprising ≥ 20% of a mixed cell population. We identified αTC1/βTC6 cis-regulatory elements orthologous to those containing type 2 diabetes (T2D)-associated SNPs in human islets for 33 loci, suggesting these cells’ utility to dissect T2D molecular genetics in these regions. Together, these maps provide important insights into the conserved regulatory architecture between αTC1/βTC6 and primary islet cells that can be leveraged in functional (epi)genomic approaches to dissect the genetic and molecular factors controlling islet cell identity and function.
Highlights
Pancreatic islets are heterogeneous clusters of endocrine cell types that secrete different hormones to control glucose homeostasis
We report the epigenome and transcriptome of alpha TC1 and beta-TC-6 islet cell models with four major goals in mind: (1) to identify cell-specific epigenome and transcriptome signatures and their hallmark features; (2) to assess the sensitivity of epigenome profiling for detecting cell-specific signatures and for reflecting relative cell proportions in a mixed cell population; (3) to elucidate the extent to which these genomic features are shared with primary mouse and human alpha and beta cells; and (4) to define the type 2 diabetes (T2D) SNP-containing regulatory elements in human islets that are functionally conserved in these cell lines and appealing targets for experimental manipulation using CRISPR/Cas9genome editing to study their function
ΒTC6 differentially accessible (DA) peaks were enriched in motifs of transcription factors (TFs) (Nkx6137–39, Isl[140,41], Pdx[142,43], and Rfx544) necessary for islet beta cell development and survival and interestingly for
Summary
Pancreatic islets are heterogeneous clusters of endocrine cell types (alpha, beta, delta, gamma/PP, and epsilon) that secrete different hormones to control glucose homeostasis. We report the epigenome and transcriptome of alpha TC1 (αTC1) and beta-TC-6 (βTC6) islet cell models with four major goals in mind: (1) to identify cell-specific epigenome and transcriptome signatures and their hallmark features; (2) to assess the sensitivity of epigenome profiling for detecting cell-specific signatures and for reflecting relative cell proportions in a mixed cell population; (3) to elucidate the extent to which these genomic features are shared with primary mouse and human alpha and beta cells; and (4) to define the T2D SNP-containing regulatory elements in human islets that are functionally conserved in these cell lines and appealing targets for experimental manipulation using CRISPR/Cas[9] (epi)genome editing to study their function Together, these detailed maps reveal both important similarities and differences between these cell models and primary islet cells and provide an important resource to guide their use in future functional genomics experiments to dissect the genetic and molecular bases for islet (dys)function and diabetes
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