Abstract
Autoimmune diabetes is a complex multifactorial disease with genetic and environmental factors playing pivotal roles. While many genes associated with the risk of diabetes have been identified to date, the mechanisms by which external triggers contribute to the genetic predisposition remain unclear. Here, we derived embryonic stem (ES) cell lines from diabetes-prone non-obese diabetic (NOD) and healthy C57BL/6 (B6) mice. While overall pluripotency markers were indistinguishable between newly derived NOD and B6 ES cells, we discovered several differentially expressed genes that normally are not expressed in ES cells. Several genes that reside in previously identified insulin-dependent diabetics (Idd) genomic regions were up-regulated in NOD ES cells. Gene set enrichment analysis showed that different groups of genes associated with immune functions are differentially expressed in NOD. Transcriptomic analysis of NOD blastocysts validated several differentially overexpressed Idd genes compared to B6. Genome-wide mapping of active histone modifications using ChIP-Seq supports active expression as the promoters and enhancers of activated genes are also marked by active histone modifications. We have also found that NOD ES cells secrete more inflammatory cytokines. Our data suggest that the known genetic predisposition of NOD to autoimmune diabetes leads to epigenetic instability of several Idd regions.
Highlights
Autoimmune diabetes, known as type-1 diabetes (T1D), is a multifactorial disease with a well-known and growing number of disease-relevant genes [1]
Given that only male embryonic stem (ES) cell lines are used for gene targeting, we focused our further characterization on male ES cell lines (NOD-5 and -6)
Using published Hi-C data in mouse embryonic stem cells [31], we found that Idd1, Idd4.2Q, Idd9.1 and Idd16.1 genes that are up-regulated in non-obese diabetic (NOD) compared to B6 localized in the same topologically associating domains (TADs), suggesting that they are transcriptionally co-regulated due to their proximity to each other and physical interaction at the genomic level (Figure 2b and Supplemental Figure S3a–d) [32]
Summary
Autoimmune diabetes, known as type-1 diabetes (T1D), is a multifactorial disease with a well-known and growing number of disease-relevant genes [1]. In addition to the genetic makeup, environmental factors are known to contribute to disease onset. Such triggers are composed of a highly heterogeneous group of factors that have been implicated to promote disease onset [7]. These include infections (e.g., enteroviruses) [8,9], birth (e.g., birth weight, or caesarean section) [10,11] and dietary factors (e.g., gluten) [12,13,14], as well as β-cell stress (e.g., overweight, puberty or trauma) [12]. It is more likely that certain environmental triggers combined with genetic risk factors increase the potential to develop T1D
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