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Published on: January 26, 2013
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A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential.
Harry Y Zhou1, Yulia Katsman1, Navroop K Dhaliwal1
1Department of Cell and Systems Biology, University of Toronto, Toronto, Ontario M5S 3G5, Canada;
Genes & Development
|December 17, 2014
Summary
A distal control region containing enhancers SRR107 and SRR111 is essential for Sox2 transcription in embryonic stem (ES) cells. Deleting this region impairs ES cell pluripotency and differentiation.
Area of Science:
- Developmental Biology
- Stem Cell Biology
- Gene Regulation
Background:
- Sox2 transcription factor is crucial for maintaining pluripotency in embryonic stem (ES) cells.
- Previously identified enhancers (SRR1, SRR2) showed limited impact on pluripotency upon deletion.
Purpose of the Study:
- To identify and functionally validate novel regulatory elements controlling Sox2 transcription in ES cells.
- To elucidate the role of distal regulatory regions in Sox2 gene cis-regulation.
Main Methods:
- Computational modeling to predict enhancer elements within 130 kb of Sox2.
- Reporter assays to validate novel enhancers (SRR18, SRR107, SRR111).
- CRISPR/Cas9 gene editing in F1 ES cells to generate enhancer deletions.
- Analysis of Sox2 mRNA and protein levels, cell morphology, gene expression, and differentiation potential.
Main Results:
- Three novel enhancers (SRR18, SRR107, SRR111) were identified and validated.
- A distal cluster containing SRR107 and SRR111, located >100 kb downstream, is critical for Sox2 cis-regulation.
- Homozygous deletion of this distal Sox2 control region (SCR) significantly reduced Sox2 levels, impaired ES cell morphology, altered genome-wide gene expression, and hindered neuroectodermal differentiation.
Conclusions:
- A distal regulatory region (SCR) containing SRR107 and SRR111 is essential for robust Sox2 transcription in ES cells.
- This distal control region plays a vital role in maintaining ES cell pluripotency and proper differentiation.
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