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Inflammatory bowel disease risk loci overlap with DNA regulatory regions in immune cells and intestinal epithelium

ABSTRACT: Background & Aims: The contribution of genetics to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin studies, targeted sequencing and genome-wide association studies (GWASs). This has yielded a plethora of risk loci with an aim to identify causal variants. Research on the genetic components of IBD has mainly focused on protein coding genes, thereby omitting other functional elements in the human genome i.e. the regulatory regions. Methods: Using acetylated histone 3 lysine 27 (H3K27ac) chromatin immunoprecipitation and sequencing (ChIP-seq), we identified tens of thousands of potential regulatory regions that are active in intestinal epithelium and immune cells, the main cell types involved in IBD. We correlated these regions with susceptibility loci for IBD. Results: We show that 45 out of 163 single nucleotide polymorphisms (SNPs) associated with IBD co-localize with active regulatory elements. In addition, another 47 IBD associated SNPs co-localize with active regulatory element via other SNP in strong linkage disequilibrium. Altogether 92 out of 163 IBD-associated SNPs can be connected with distinct regulatory element. This is 2.5 to 3.5 times more frequent than expected from random sampling. The genomic variation in these SNPs often creates or disrupts known binding motifs - thereby possibly affecting the binding affinity of transcriptional regulators and altering the expression of regulated genes. Conclusions: We show that in addition to protein coding genes, non-coding DNA regulatory regions, active in immune cells and in intestinal epithelium, are involved in IBD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE51425 | GEO | 2013/12/06

SECONDARY ACCESSION(S): PRJNA223151

REPOSITORIES: GEO

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Project description:Objective: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF) PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4). Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs) and T2DM and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. Methods: In this study, we have generated a novel induced pluripotent stem cell (iPSC) line that efficiently differentiates into human pancreatic progenitors (PPs). Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq) was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. Results: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions included important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B and MEIS1, which were activated during the differentiation process as revealed by the active mono-acetylated chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation maintains PDX1 expression and initiates a pancreatic TF program. Remarkably, we identified several PDX1 target genes that have not been reported in human so far, including RFX3, required for ciliogenesis and endocrine differentiation in mouse, and the ligand for the Notch receptor, DLL1, which is important for endocrine induction and tip-trunk patterning. The comparison of PDX1 profiles from PPs and adult human islets identified sets of stage-specific target genes, associated with early pancreas development and adult β-cell function. Furthermore, we found an enrichment of T2DM-associated SNPs in active chromatin regions from iPSC-derived PPs. Two of these SNPs fall into PDX1 occupied sites that are located in the intronic regions of TCF7L2 and HNF1B. Both of these genes are key transcriptional regulators of endocrine induction and mutations in cis-regulatory regions predispose to diabetes. Conclusions: Our data provides stage-specific target genes of PDX1 during in vitro differentiation of stem cells into pancreatic progenitors that could be useful to identify pathways and molecular targets that predispose for diabetes. In addition, we show that T2DM-associated SNPs are enriched in active chromatin regions at the pancreatic progenitor stage, suggesting that the susceptibility to T2DM might originate from imperfect execution of a β-cell developmental program.

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Inflammatory bowel disease risk loci overlap with DNA regulatory regions in immune cells and intestinal epithelium

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