Smarcc1/Baf155 Couples Self‐Renewal Gene Repression with Changes in Chromatin Structure in Mouse Embryonic Stem Cells

Little is known about the molecular mechanism(s) governing differentiation decisions in embryonic stem cells (ESCs). To identify factors critical for ESC lineage formation, we carried out a functional genetic screen for factors affecting Nanog promoter activity during mESC differentiation. We report...

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Published in:Stem cells (Dayton, Ohio) Ohio), 2009-12, Vol.27 (12), p.2979-2991
Main Authors: Schaniel, Christoph, Ang, Yen‐Sin, Ratnakumar, Kajan, Cormier, Catherine, James, Taneisha, Bernstein, Emily, Lemischka, Ihor R., Paddison, Patrick J.
Format: Article
Language:English
Subjects:
Animals
Cell Differentiation
Cell Line
Chromatin - genetics
Chromatin - metabolism
Chromosomal Proteins, Non-Histone - metabolism
Differentiation
Embryonic Stem Cells - cytology
Embryonic Stem Cells - metabolism
ESC
Functional genetics
Gene Expression Regulation
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Mice
Nanog
Nanog Homeobox Protein
Protein Binding
RNAi
Smarcc1
Transcription Factors - genetics
Transcription Factors - metabolism
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Summary:Little is known about the molecular mechanism(s) governing differentiation decisions in embryonic stem cells (ESCs). To identify factors critical for ESC lineage formation, we carried out a functional genetic screen for factors affecting Nanog promoter activity during mESC differentiation. We report that members of the PBAF chromatin remodeling complex, including Smarca4/Brg1, Smarcb1/Baf47, Smarcc1/Baf155, and Smarce1/Baf57, are required for the repression of Nanog and other self‐renewal gene expression upon mouse ESC (mESC) differentiation. Knockdown of Smarcc1 or Smarce1 suppressed loss of Nanog expression in multiple forms of differentiation. This effect occurred in the absence of self‐renewal factors normally required for Nanog expression (e.g., Oct4), possibly indicating that changes in chromatin structure, rather than loss of self‐renewal gene transcription per se, trigger differentiation. Consistent with this notion, mechanistic studies demonstrated that expression of Smarcc1 is necessary for heterochromatin formation and chromatin compaction during differentiation. Collectively, our data reveal that Smarcc1 plays important roles in facilitating mESCs differentiation by coupling gene repression with global and local changes in chromatin structure. STEM CELLS 2009;27:2979–2991
ISSN:1066-5099
1549-4918
DOI:10.1002/stem.223