title: Chronic inflammation induces a novel epigenetic program that is conserved in intestinal adenomas and in colorectal cancer.
abstract: Chronic inflammation represents a major risk factor for tumor formation, but the underlying mechanisms have remained largely unknown. Epigenetic mechanisms can record the effects of environmental challenges on the genome level and could therefore play an important role in the pathogenesis of inflammation-associated tumors. Using single-base methylation maps and transcriptome analyses of a colitis-induced mouse colon cancer model, we identified a novel epigenetic program that is characterized by hypermethylation of DNA methylation valleys that are characterized by low CpG density and active chromatin marks. This program is conserved and functional in mouse intestinal adenomas and results in silencing of active intestinal genes that are involved in gastrointestinal homeostasis and injury response. Further analyses reveal that the program represents a prominent feature of human colorectal cancer and can be used to correctly classify colorectal cancer samples with high accuracy. Together, our results show that inflammatory signals establish a novel epigenetic program that silences a specific set of genes that contribute to inflammation-induced cellular transformation.
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors: Monther
authors: M
authors: Abu-Remaileh
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors: Sebastian
authors: S
authors: Bender
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors: Günter
authors: G
authors: Raddatz
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors: Ihab
authors: I
authors: Ansari
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors: Daphne
authors: D
authors: Cohen
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors: Julian
authors: J
authors: Gutekunst
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors: Tanja
authors: T
authors: Musch
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. Salem Medical Center, University of Heidelberg, Heidelberg, Germany. Department of Hematology/Oncology, University of Heidelberg Medical Center, Heidelberg, Germany.
authors: Heinz
authors: H
authors: Linhart
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany.
authors: Achim
authors: A
authors: Breiling
authors: The Lautenberg Center for Immunology, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel.
authors: Eli
authors: E
authors: Pikarsky
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University Medical School, Jerusalem, Israel. f.lyko@dkfz.de yehuditb@ekmd.huji.ac.il.
authors: Yehudit
authors: Y
authors: Bergman
authors: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Heidelberg, Germany. f.lyko@dkfz.de yehuditb@ekmd.huji.ac.il.
authors: Frank
authors: F
authors: Lyko
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000236:Adenoma / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D000818:Animals; D003092:Colitis / Q000235:genetics* / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL