Sox2 acts through Sox21 to regulate transcription in pluripotent and differentiated cells.
Sox2 is an important transcriptional regulator in embryonic and adult stem cells. Recently, Sox2 was identified as an oncogene in many endodermal cancers, including colon cancer. There is great interest in how Sox2 cooperates with other transcription factors to regulate stem cell renewal, differentiation, and reprogramming. However, we still lack a general understanding of Sox2 transcriptional action. To determine transcriptional partners of Sox2 in adult cells, we generated mice where gene expression could be induced by an externally applied stimulus. We analyzed the consequences in the intestine where cell turnover is rapid. Sox2 expression, but not Oct4, specifically increased the numbers of stem cells and repressed Cdx2, a master regulator of endodermal identity. In vivo studies demonstrated that Sox21, another member of the SoxB gene family, was a specific, immediate, and cell-autonomous target of Sox2 in intestinal stem cells. In vitro experiments showed that Sox21 was sufficient to repress Cdx2 in colon cancer cells and in pluripotent stem cells. Sox21 was also specifically induced by Sox2 in fibroblasts and inhibition of Sox21 blocked reprogramming to the pluripotent state. These results show that transcriptional induction of Sox21 is a rapid and general mediator of the effects of Sox2 on cell identity in a wide range of cell types.
Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
Andrey N
AN
Kuzmichev
Suel-Kee
SK
Kim
Ana C
AC
D'Alessio
Josh G
JG
Chenoweth
Ina M
IM
Wittko
Loraine
L
Campanati
Ronald D
RD
McKay
D000818:Animals; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D051379:Mice; D008822:Mice, Transgenic; D050814:Octamer Transcription Factor-3 / Q000096:biosynthesis; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism*; D055749:SOXB2 Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D050814:Octamer Transcription Factor-3; C494174:Pou5f1 protein, mouse; D055748:SOXB1 Transcription Factors; D055749:SOXB2 Transcription Factors; C527783:Sox2 protein, mouse; C484489:Sox21 protein, mouse; D014157:Transcription Factors