title: DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC.
abstract: Although genome-wide hypomethylation is a hallmark of many cancers, roles for active DNA demethylation during tumorigenesis are unknown. Here, loss of the APC tumor suppressor gene causes upregulation of a DNA demethylase system and the concomitant hypomethylation of key intestinal cell fating genes. Notably, this hypomethylation maintained zebrafish intestinal cells in an undifferentiated state that was released upon knockdown of demethylase components. Mechanistically, the demethylase genes are directly activated by Pou5f1 and Cebpβ and are indirectly repressed by retinoic acid, which antagonizes Pou5f1 and Cebpβ. Apc mutants lack retinoic acid as a result of the transcriptional repression of retinol dehydrogenase l1 via a complex that includes Lef1, Groucho2, Ctbp1, Lsd1, and Corest. Our findings imply a model wherein APC controls intestinal cell fating through a switch in DNA methylation dynamics. Wild-type APC and retinoic acid downregulate demethylase components, thereby promoting DNA methylation of key genes and helping progenitors commit to differentiation.
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kunal
authors.initials: K
authors.lastname: Rai
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Sarkar
authors.forename: Talmage J
authors.initials: TJ
authors.lastname: Broadbent
authors.forename: Matthew
authors.initials: M
authors.lastname: Voas
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Grossmann
authors.forename: Lincoln D
authors.initials: LD
authors.lastname: Nadauld
authors.forename: Somaye
authors.initials: S
authors.lastname: Dehghanizadeh
authors.forename: Fanuel T
authors.initials: FT
authors.lastname: Hagos
authors.forename: Yumei
authors.initials: Y
authors.lastname: Li
authors.forename: Rachel K
authors.initials: RK
authors.lastname: Toth
authors.forename: Stephanie
authors.initials: S
authors.lastname: Chidester
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Bahr
authors.forename: W Evan
authors.initials: WE
authors.lastname: Johnson
authors.forename: Brad
authors.initials: B
authors.lastname: Sklow
authors.forename: Randall
authors.initials: R
authors.lastname: Burt
authors.forename: Bradley R
authors.initials: BR
authors.lastname: Cairns
authors.forename: David A
authors.initials: DA
authors.lastname: Jones
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000378:metabolism* / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000378:metabolism*; D000429:Alcohol Oxidoreductases / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000166:cytology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D056970:Co-Repressor Proteins / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D019175:DNA Methylation; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000196:embryology*; D050814:Octamer Transcription Factor-3 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014212:Tretinoin / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D022782:CCAAT-Enhancer-Binding Protein-beta; D056970:Co-Repressor Proteins; D050814:Octamer Transcription Factor-3; D014157:Transcription Factors; D014212:Tretinoin; D000429:Alcohol Oxidoreductases; C022520:retinol dehydrogenase