TY - JOUR
T1 - Many inflammatory bowel disease risk loci include regions that regulate gene expression in immune cells and the intestinal epithelium
AU - Mokry, Michal
AU - Middendorp, Sabine
AU - Wiegerinck, Caroline L
AU - Witte, Merlijn
AU - Teunissen, Hans
AU - Meddens, Claartje A
AU - Cuppen, Edwin
AU - Clevers, Hans
AU - Nieuwenhuis, Edward E S
N1 - Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
PY - 2014/4
Y1 - 2014/4
N2 - BACKGROUND & AIMS: The contribution of genetic factors to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin, targeted-sequencing, and genome-wide association studies. These studies identified many risk loci, and research is underway to identify causal variants. These studies have focused mainly on protein-coding genes. We investigated other functional elements in the human genome, such as regulatory regions.METHODS: Using acetylated histone 3 lysine 27 chromatin immunoprecipitation and sequencing, we identified tens of thousands of potential regulatory regions that are active in intestinal epithelium (primary intestinal crypts and cultured organoids) isolated from resected material and from biopsies collected during ileo-colonoscopies and immune cells (monocytes, macrophages, CD34(+), CD4(+), and CD8(+)). We correlated these regions with susceptibility loci for IBD.RESULTS: We have generated acetylated histone 3 lysine 27 profiles from primary intestinal epithelium and cultured organoids, which we have made publically available. We found that 45 of 163 single nucleotide polymorphisms (SNPs) associated with IBD overlap specifically with active regulatory elements. In addition, by taking strong linkage disequilibrium into account, another 47 IBD-associated SNPs colocalized with active regulatory elements through other SNPs in their vicinity. Altogether, 92 of 163 IBD-associated SNPs correlated with distinct active regulatory elements-a frequency 2.5- to 3.5-fold greater than that expected from random sampling. The variations in these SNPs often create or disrupt known binding motifs; they might affect the binding of transcriptional regulators to alter expression of regulated genes.CONCLUSIONS: In addition to variants in protein coding genes, variants in noncoding DNA regulatory regions that are active in intestinal epithelium and immune cells are potentially involved in the pathogenesis of IBD.
AB - BACKGROUND & AIMS: The contribution of genetic factors to the pathogenesis of inflammatory bowel disease (IBD) has been established by twin, targeted-sequencing, and genome-wide association studies. These studies identified many risk loci, and research is underway to identify causal variants. These studies have focused mainly on protein-coding genes. We investigated other functional elements in the human genome, such as regulatory regions.METHODS: Using acetylated histone 3 lysine 27 chromatin immunoprecipitation and sequencing, we identified tens of thousands of potential regulatory regions that are active in intestinal epithelium (primary intestinal crypts and cultured organoids) isolated from resected material and from biopsies collected during ileo-colonoscopies and immune cells (monocytes, macrophages, CD34(+), CD4(+), and CD8(+)). We correlated these regions with susceptibility loci for IBD.RESULTS: We have generated acetylated histone 3 lysine 27 profiles from primary intestinal epithelium and cultured organoids, which we have made publically available. We found that 45 of 163 single nucleotide polymorphisms (SNPs) associated with IBD overlap specifically with active regulatory elements. In addition, by taking strong linkage disequilibrium into account, another 47 IBD-associated SNPs colocalized with active regulatory elements through other SNPs in their vicinity. Altogether, 92 of 163 IBD-associated SNPs correlated with distinct active regulatory elements-a frequency 2.5- to 3.5-fold greater than that expected from random sampling. The variations in these SNPs often create or disrupt known binding motifs; they might affect the binding of transcriptional regulators to alter expression of regulated genes.CONCLUSIONS: In addition to variants in protein coding genes, variants in noncoding DNA regulatory regions that are active in intestinal epithelium and immune cells are potentially involved in the pathogenesis of IBD.
KW - Acetylation
KW - Animals
KW - Animals, Genetically Modified
KW - Chromatin Immunoprecipitation
KW - Gene Expression Regulation
KW - Genetic Loci
KW - Genetic Predisposition to Disease
KW - Genome-Wide Association Study
KW - Histones
KW - Humans
KW - Immunity, Mucosal
KW - Inflammatory Bowel Diseases
KW - Intestinal Mucosa
KW - Linkage Disequilibrium
KW - Phenotype
KW - Polymorphism, Single Nucleotide
KW - Regulatory Sequences, Nucleic Acid
KW - Reproducibility of Results
KW - Risk Factors
KW - Sequence Analysis, DNA
KW - Zebrafish
U2 - 10.1053/j.gastro.2013.12.003
DO - 10.1053/j.gastro.2013.12.003
M3 - Article
C2 - 24333384
SN - 0016-5085
VL - 146
SP - 1040
EP - 1047
JO - Gastroenterology
JF - Gastroenterology
IS - 4
ER -