title: Long range epigenetic silencing is a trans-species mechanism that results in cancer specific deregulation by overriding the chromatin domains of normal cells.
abstract: DNA methylation and chromatin remodeling are frequently implicated in the silencing of genes involved in carcinogenesis. Long Range Epigenetic Silencing (LRES) is a mechanism of gene inactivation that affects multiple contiguous CpG islands and has been described in different human cancer types. However, it is unknown whether there is a coordinated regulation of the genes embedded in these regions in normal cells and in early stages of tumor progression. To better characterize the molecular events associated with the regulation and remodeling of these regions we analyzed two regions undergoing LRES in human colon cancer in the mouse model. We demonstrate that LRES also occurs in murine cancer in vivo and mimics the molecular features of the human phenomenon, namely, downregulation of gene expression, acquisition of inactive histone marks, and DNA hypermethylation of specific CpG islands. The genes embedded in these regions showed a dynamic and autonomous regulation during mouse intestinal cell differentiation, indicating that, in the framework considered here, the coordinated regulation in LRES is restricted to cancer. Unexpectedly, benign adenomas in Apc(Min/+) mice showed overexpression of most of the genes affected by LRES in cancer, which suggests that the repressive remodeling of the region is a late event. Chromatin immunoprecipitation analysis of the transcriptional insulator CTCF in mouse colon cancer cells revealed disrupted chromatin domain boundaries as compared with normal cells. Malignant regression of cancer cells by in vitro differentiation resulted in partial reversion of LRES and gain of CTCF binding. We conclude that genes in LRES regions are plastically regulated in cell differentiation and hyperproliferation, but are constrained to a coordinated repression by abolishing boundaries and the autonomous regulation of chromatin domains in cancer cells.
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer (IMPPC), 08916 Badalona, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Forn
authors.forename: Mar
authors.initials: M
authors.lastname: Muñoz
authors.forename: Daniele V F
authors.initials: DV
authors.lastname: Tauriello
authors.forename: Anna
authors.initials: A
authors.lastname: Merlos-Suárez
authors.forename: Verónica
authors.initials: V
authors.lastname: Rodilla
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.forename: Eduard
authors.initials: E
authors.lastname: Batlle
authors.forename: Mireia
authors.initials: M
authors.lastname: Jordà
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Peinado
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002843:Chromatin / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D002843:Chromatin; D004273:DNA, Neoplasm; D006657:Histones; D009363:Neoplasm Proteins
keywords: Cell differentiation; ChIP; Chromatin immunoprecipitation; Chromatin marks; Colorectal cancer; DNA methylation; Gene silencing; Histone modification; ISC; Intestinal stem cells; LRES; Long range epigenetic silencing
references.citation: Mol Biol Cell. 2007 Nov;18(11):4245-60
references.pmid: 17699589
references.citation: Clin Cancer Res. 2009 Sep 15;15(18):5762-71
references.pmid: 19737964
references.citation: Nat Genet. 2006 Dec;38(12):1386-96
references.pmid: 17099711
references.citation: Cell. 2005 Jan 28;120(2):169-81
references.pmid: 15680324
references.citation: Vitam Horm. 2011;85:79-104
references.pmid: 21353877
references.citation: Mol Oncol. 2013 Dec;7(6):1129-41
references.pmid: 24035705
references.citation: Cancer Res. 2003 Sep 15;63(18):5731-7
references.pmid: 14522893
references.citation: Nat Genet. 2009 Feb;41(2):178-186
references.pmid: 19151715
references.citation: Nat Cell Biol. 2010 Mar;12(3):235-46
references.pmid: 20173741
references.citation: Mol Cell Biol. 2010 Mar;30(5):1199-216
references.pmid: 20038529
references.citation: Nature. 2009 Jan 29;457(7229):608-11
references.pmid: 19092804
references.citation: Gene. 2005 Oct 10;359:127-37
references.pmid: 16162394
references.citation: Nature. 2008 Aug 7;454(7205):766-70
references.pmid: 18600261
references.citation: N Engl J Med. 2008 Mar 13;358(11):1148-59
references.pmid: 18337604
references.citation: Cancer Res. 2007 Oct 1;67(19):9107-16
references.pmid: 17909015
references.citation: Nat Biotechnol. 2010 Oct;28(10):1057-68
references.pmid: 20944598
references.citation: Mamm Genome. 2011 Apr;22(3-4):249-59
references.pmid: 21373886
references.citation: Nat Cell Biol. 2006 May;8(5):532-8
references.pmid: 16570078
references.citation: Nature. 2007 Aug 2;448(7153):553-60
references.pmid: 17603471
references.citation: J Biol Chem. 2003 Jul 25;278(30):27658-62
references.pmid: 12724318
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19809-14
references.pmid: 19060200
references.citation: Nat Genet. 2007 Feb;39(2):237-42
references.pmid: 17211412
references.citation: Epigenetics. 2011 Nov;6(11):1344-53
references.pmid: 22048248
references.citation: Mol Cell. 2008 Jun 20;30(6):755-66
references.pmid: 18514006
references.citation: PLoS Genet. 2009 Nov;5(11):e1000745
references.pmid: 19956686
references.citation: Cell. 2006 Apr 21;125(2):315-26
references.pmid: 16630819
references.citation: Hum Mol Genet. 2007 Apr 15;16 Spec No 1:R88-95
references.pmid: 17613553
references.citation: Nucleic Acids Res. 1991 May 11;19(9):2499
references.pmid: 2041787
references.citation: Cell Stem Cell. 2011 May 6;8(5):511-24
references.pmid: 21419747
references.citation: Cell. 2007 Feb 23;128(4):683-92
references.pmid: 17320506
references.citation: Nature. 2006 Feb 16;439(7078):871-4
references.pmid: 16357870
references.citation: J Biol Chem. 2010 Apr 23;285(17):13193-200
references.pmid: 20159971
references.citation: Epigenetics. 2011 Sep 1;6(9):1138-48
references.pmid: 21852760
references.citation: Br J Cancer. 2009 May 19;100(10):1534-9
references.pmid: 19384295
references.citation: Cell. 2007 May 18;129(4):823-37
references.pmid: 17512414
references.citation: J Clin Endocrinol Metab. 2007 Nov;92(11):4394-402
references.pmid: 17711922
references.citation: Science. 2012 Aug 10;337(6095):730-5
references.pmid: 22855427
references.citation: BMC Med Genomics. 2011 Dec 02;4:82
references.pmid: 22133303
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6315-20
references.pmid: 19325125
references.citation: Oncogene. 2012 Oct 4;31(40):4409-19
references.pmid: 22249255
references.citation: Mol Cancer Res. 2011 Aug;9(8):1139-51
references.pmid: 21737484
references.citation: Nat Genet. 2011 Nov 27;44(1):40-6
references.pmid: 22120008
references.citation: Cancer Res. 2008 Oct 15;68(20):8616-25
references.pmid: 18922938
references.citation: Mol Carcinog. 2008 Sep;47(9):701-6
references.pmid: 18176935
references.citation: PLoS Genet. 2013;9(2):e1003250
references.pmid: 23408899
references.citation: PLoS One. 2012;7(6):e39371
references.pmid: 22724006
references.citation: Cancer Res. 2005 Jun 15;65(12):5112-22
references.pmid: 15958555
references.citation: Cell. 2012 Jun 8;149(6):1381-92
references.pmid: 22682255
references.citation: Cell. 2007 Mar 23;128(6):1231-45
references.pmid: 17382889
references.citation: Genome Res. 2010 Jun;20(6):733-44
references.pmid: 20442245
references.citation: Cancer Res. 2002 Dec 15;62(24):7213-8
references.pmid: 12499261
references.citation: J Biol Chem. 2005 Jul 29;280(30):28152-61
references.pmid: 15941718
references.citation: Nat Genet. 2006 May;38(5):540-9
references.pmid: 16642018
references.citation: Nat Genet. 2011 Jun 26;43(8):768-75
references.pmid: 21706001
references.citation: Mol Oncol. 2009 Feb;3(1):54-66
references.pmid: 19383367
references.citation: FEBS Lett. 1999 Feb 5;444(1):5-10
references.pmid: 10037138