DNA demethylase activity maintains intestinal cells in an undifferentiated state following loss of APC.
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.
Rai
Kunal
K
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Sarkar
Sharmistha
S
Broadbent
Talmage J
TJ
Voas
Matthew
M
Grossmann
Kenneth F
KF
Nadauld
Lincoln D
LD
Dehghanizadeh
Somaye
S
Hagos
Fanuel T
FT
Li
Yumei
Y
Toth
Rachel K
RK
Chidester
Stephanie
S
Bahr
Timothy M
TM
Johnson
W Evan
WE
Sklow
Brad
B
Burt
Randall
R
Cairns
Bradley R
BR
Jones
David A
DA
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*
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