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      Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

      , , ,

      Gastroenterology

      W.B. Saunders

      Epigenetics, Crohn’s Disease, Ulcerative Colitis, DNA Methylation, CD, Crohn’s disease, CpG, cytosine-guanine dinucleotides, DNMT, DNA methyltransferase, EWAS, epigenome-wide methylation association studies, GWAS, genome-wide association studies, HAT, histone acetyl transferase, HDAC, histone deacetylase, HDACi, histone deacetylatase inhibitors, IBD, inflammatory bowel disease, IL, interleukin, miR, microRNA, mRNA, messenger RNA, NF-κB, nuclear factor κB, PBMC, peripheral blood mononuclear cell, SNP, single nucleotide polymorphism, Th, T-helper, TNF, tumor necrosis factor, UC, ulcerative colitis

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          Abstract

          In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.

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          Most cited references 107

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          Physiological and pathological roles for microRNAs in the immune system.

          Mammalian microRNAs (miRNAs) have recently been identified as important regulators of gene expression, and they function by repressing specific target genes at the post-transcriptional level. Now, studies of miRNAs are resolving some unsolved issues in immunology. Recent studies have shown that miRNAs have unique expression profiles in cells of the innate and adaptive immune systems and have pivotal roles in the regulation of both cell development and function. Furthermore, when miRNAs are aberrantly expressed they can contribute to pathological conditions involving the immune system, such as cancer and autoimmunity; they have also been shown to be useful as diagnostic and prognostic indicators of disease type and severity. This Review discusses recent advances in our understanding of both the intended functions of miRNAs in managing immune cell biology and their pathological roles when their expression is dysregulated.
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            Epigenome-wide association studies for common human diseases.

            Despite the success of genome-wide association studies (GWASs) in identifying loci associated with common diseases, a substantial proportion of the causality remains unexplained. Recent advances in genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, specifically variation in DNA methylation. Such epigenome-wide association studies (EWASs) present novel opportunities but also create new challenges that are not encountered in GWASs. We discuss EWAS design, cohort and sample selections, statistical significance and power, confounding factors and follow-up studies. We also discuss how integration of EWASs with GWASs can help to dissect complex GWAS haplotypes for functional analysis.
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              Epigenetic inheritance at the agouti locus in the mouse.

              Epigenetic modifications have effects on phenotype, but they are generally considered to be cleared on passage through the germ line in mammals, so that only genetic traits are inherited. Here we describe the inheritance of an epigenetic modification at the agouti locus in mice. In viable yellow ( A(vy)/a) mice, transcription originating in an intra-cisternal A particle (IAP) retrotransposon inserted upstream of the agouti gene (A) causes ectopic expression of agouti protein, resulting in yellow fur, obesity, diabetes and increased susceptibility to tumours. The pleiotropic effects of ectopic agouti expression are presumably due to effects of the paracrine signal on other tissues. Avy mice display variable expressivity because they are epigenetic mosaics for activity of the retrotransposon: isogenic Avy mice have coats that vary in a continuous spectrum from full yellow, through variegated yellow/agouti, to full agouti (pseudoagouti). The distribution of phenotypes among offspring is related to the phenotype of the dam; when an A(vy) dam has the agouti phenotype, her offspring are more likely to be agouti. We demonstrate here that this maternal epigenetic effect is not the result of a maternally contributed environment. Rather, our data show that it results from incomplete erasure of an epigenetic modification when a silenced Avy allele is passed through the female germ line, with consequent inheritance of the epigenetic modification. Because retrotransposons are abundant in mammalian genomes, this type of inheritance may be common.
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                Author and article information

                Contributors
                Journal
                Gastroenterology
                Gastroenterology
                Gastroenterology
                W.B. Saunders
                0016-5085
                1528-0012
                1 August 2013
                August 2013
                : 145
                : 2
                : 293-308
                Affiliations
                Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland
                Author notes
                [] Reprint requests Address requests for reprints to: Nicholas T. Ventham, Gastrointestinal Unit, Centre for Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, Scotland. fax: +44 131 651 1085. nventham@ 123456staffmail.ed.ac.uk
                Article
                S0016-5085(13)00850-0
                10.1053/j.gastro.2013.05.050
                3919211
                23751777
                © 2013 Elsevier Inc.

                This document may be redistributed and reused, subject to certain conditions.

                Categories
                Reviews and Perspectives
                Reviews in Basic and Clinical Gastroenterology and Hepatology

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