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Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies

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

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Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies

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  1. Epigenetic regulation of IBD-associated fibrosis: potential for novel anti-fibrotic therapies Tammy Sadler1,2, Angela Ting3, Yaomin Xu4, Xiuli Liu5, Eleni Stylianou1,2 1Department of Pathobiology, Lerner Research Institute, and 2Department of Gastroenterology and Hepatology, Digestive Disease Institute, 3Genomic Medicine Institute, 4Department of Quantitative Health Sciences, 5Department of Anatomic Pathology. Cleveland Clinic Foundation, Cleveland, USA

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

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

  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. Epigenetic regulation of gene transcription Repressed, histone/DNA methylated promoter: condensed chromatin (heterochromatin) Histone-modified, remodelled, decondensed promoter (euchromatin) Accessible, transcriptionally active promoter IL-1b LPS TNF-a K9me K27me H3 H4 DNA methylation Corepressors Coactivators RNA Pol II K4me K4me H3 H3 Kac Kac H4 H4 Scarpa & Stylianou Inflamm Bowel Dis 2012

  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. Specific histone modifications are associated with induction of COL1A2 gene expression in intestinal EndoMT Ac Ac Ac A IL1b TGFb Ac Ac Ac 8 8 H4 H4 12 12 16 16 TNFa Me Me Me Me COL1A2 H3 9 H3 9 5 days Ac Ac Ac Ac Ac 5 Ac 8 Ac 5 Ac H4 B TGFb IL1b -1599bp H4 -25bp 12 12 16 16 TNFa H3 H3 COL1A2 16 days Ac Ac H4 Cytokines removed after 16 days + 10 day washoff H4 16 C H3 Ac H3 Ac 8 COL1A2 Sadler et al Inflamm Bowel Dis 2013 in press

  8. Hypothesis and Aims 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.

  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. Intestinal tissue specimens procured during year 1

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