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Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies Tammy Sadler 1,2, Angela Ting 3, Yaomin Xu 4, Xiuli Liu 5,

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Presentation on theme: "Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies Tammy Sadler 1,2, Angela Ting 3, Yaomin Xu 4, Xiuli Liu 5,"— Presentation transcript:

1 Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies Tammy Sadler 1,2, Angela Ting 3, Yaomin Xu 4, Xiuli Liu 5, Eleni Stylianou 1,2 1 Department of Pathobiology, Lerner Research Institute, and 2 Department of Gastroenterology and Hepatology, Digestive Disease Institute, 3 Genomic Medicine Institute, 4 Department of Quantitative Health Sciences, 5 Department of Anatomic Pathology. Cleveland Clinic Foundation, Cleveland, USA

2 Crohns Disease Inflammation of small bowel & colon: transmural Environmental factors Genetic susceptibility Abnormal interaction of commensal gut flora, epithelial barrier and innate immunity Inflammatory Bowel Disease – etiology? FIBROSIS Increased matrix depostion e.g.Type I collagen (COL1A1, COL1A2) EPIGENETICS?

3 Endothelial cells Mucosal innate immune cells Mesenchymal cells/fibroblasts/myofibrobla sts Epithelium Apoptotic & necrotic epithelial cells GUT LUMEN Gut flora SUBMUCOS A FIBROSIS Intestinal inflammation and fibrosis in IBD Epithelial barrier dysfunction Cytokines, chemokines e.g TNF, IL-8, TGF, IL-1, IL-17 Endogenous signals Cytokines TYPE I COLLAGEN

4 Epigenetics Heritable changes in phenotype that are independent of changes to the DNA sequence 2 examples: Histone modifications and DNA methylation Epigenetic mechanisms determine whether a gene is silenced or activated and allows the cell to adapt to environmental cues. Epigenetics bridges the gap between genotype and environment

5 K9 me H3 H4 K27 me Corepressors K4 me H3 H4 K ac RNA Pol II Coactivators LPS IL- TNF- K4 me H3 H4 K ac Repressed, histone/DNA methylated promoter: condensed chromatin (heterochromatin) Histone-modified, remodelled, decondensed promoter (euchromatin) Accessible, transcriptionally active promoter DNA methylation Scarpa & Stylianou Inflamm Bowel Dis 2012 Epigenetic regulation of gene transcription

6 Clinical Significance Epigenetic modifications required for Type I collagen gene expression and a fibrotic DNA methylome or epigenotype for CD could have diagnostic and prognostic utility. New mechanistic insights into clinically relevant mechanisms of disease pathogenesis could be provided. The conceptual framework for identification of therapeutic targets and selective and efficacious anti- fibrotic "epi-pharmaceuticals that could prevent or treat fibrosis.

7 COL1A2 H4 H3 Ac 16 H4 H Ac 8 TGF H4 H3 Ac 16 H4 H3 COL1A2 Ac Cytokines removed after 16 days + 10 day washoff -1599bp -25bp IL1 TNF H4 H3 Ac H4 H3 Ac Me 9 COL1A2 Ac IL1 TNF TGF 5 days 16 days Specific histone modifications are associated with induction of COL1A2 gene expression in intestinal EndoMT Me 9 Ac 8 12 Ac 5 5 A B C Sadler et al Inflamm Bowel Dis 2013 in press

8 Fibrosis-specific epigenetic signatures occur in the fibrotic intestine in IBD. This hypothesis will be tested by 2 specific aims: Aim 1. Determine the fibrosis-specific histone modification signature in human fibrotic intestine in IBD in vivo. Aim 2. Identify the fibrosis-specific DNA methylome that defines human intestinal fibrogenesis in IBD in vivo. Hypothesis and Aims

9 Research plan Year 1 Collect age and gender matched normal control and CD fibrotic tissue specimens Optimize conditions for ChIP of tissue Establish conditions for isolation of fresh human fibroblasts Demonstrate feasibility of performing epigenetic analysis in fresh HIF Year 2 ChIP assays of tissue and fresh HIF to define type I collagen specific histone modification signature Employ MBD-isolated genome sequencing (MiGS) to profile changes in DNA methylation in human fibroblasts from fibrotic intestine. Integrate methylome with fibrotic transcriptome

10 Tissue sourceDiagnosisNumber of specimens ColonDiverticular disease7 Polyps3 UC inflamed8 CD fibrotic10 CD inflamed5 IleumPolyps1 Ileocolic anastamosis1 CD fibrotic8 CD inflamed4 Intestinal tissue specimens procured during year 1


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