Oct4 switches partnering from Sox2 to Sox17 to reinterpret the enhancer code and specify endoderm

被引：145

作者：

Aksoy, Irene ^{[1
]}

Jauch, Ralf ^{[2
]}

Chen, Jiaxuan ^{[1
]}

Dyla, Mateusz ^{[2
]}

Divakar, Ushashree ^{[1
]}

Bogu, Gireesh K. ^{[1
]}

Teo, Roy ^{[1
]}

Ng, Calista Keow Leng ^{[2
,3
]}

Herath, Wishva ^{[1
]}

Sun Lili ^{[1
]}

Hutchins, Andrew P. ^{[1
,4
]}

Robson, Paul ^{[1
,5
]}

Kolatkar, Prasanna R. ^{[1
,2
,5
]}

Stanton, Lawrence W. ^{[1
,3
,5
]}

机构：

[1] Genome Inst Singapore, Singapore 138672, Singapore

[2] Genome Inst Singapore, Lab Struct Biochem, Singapore 138672, Singapore

[3] Nanyang Technol Univ, Sch Biol Sci, Singapore 639798, Singapore

[4] Osaka Univ, Immunol Frontier Res Ctr, Osaka, Japan

[5] Natl Univ Singapore, Dept Biol Sci, Singapore 117548, Singapore

来源：

EMBO JOURNAL | 2013年 / 32卷 / 07期

关键词：

endoderm; enhancer code; lineage specification; pluripotency; Sox/Oct interaction; TRANSCRIPTION FACTOR; GENE-EXPRESSION; POU PROTEINS; STEM-CELLS; DIFFERENTIATION; IDENTIFICATION; DISTINCT; ESTABLISHMENT; INTEGRATION; PROMOTERS;

D O I：

10.1038/emboj.2013.31

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

How regulatory information is encoded in the genome is poorly understood and poses a challenge when studying biological processes. We demonstrate here that genomic redistribution of Oct4 by alternative partnering with Sox2 and Sox17 is a fundamental regulatory event of endodermal specification. We show that Sox17 partners with Oct4 and binds to a unique 'compressed' Sox/Oct motif that earmarks endodermal genes. This is in contrast to the pluripotent state where Oct4 selectively partners with Sox2 at 'canonical' binding sites. The distinct selection of binding sites by alternative Sox/Oct partnering is underscored by our demonstration that rationally point-mutated Sox17 partners with Oct4 on pluripotency genes earmarked by the canonical Sox/Oct motif. In an endodermal differentiation assay, we demonstrate that the compressed motif is required for proper expression of endodermal genes. Evidently, Oct4 drives alternative developmental programs by switching Sox partners that affects enhancer selection, leading to either an endodermal or pluripotent cell fate. This work provides insights in understanding cell fate transcriptional regulation by highlighting the direct link between the DNA sequence of an enhancer and a developmental outcome. The EMBO Journal (2013) 32, 938-953. doi:10.1038/emboj.2013.31; Published online 8 March 2013

引用

页码：938 / 953

页数：16

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