A Sox2 distal enhancer cluster regulates embryonic stem cell differentiation potential
Open accessAbstract
The Sox2 transcription factor must be robustly transcribed in embryonic stem (ES) cells to maintain pluripotency. Two gene-proximal enhancers, Sox2 regulatory region 1 (SRR1) and SRR2, display activity in reporter assays, but deleting SRR1 has no effect on pluripotency. We identified and functionally validated the sequences required for Sox2 transcription based on a computational model that predicted transcriptional enhancer elements within 130 kb of Sox2 . Our reporter assays revealed three novel enhancers—SRR18, SRR107, and SRR111—that, through the formation of chromatin loops, form a chromatin complex with the Sox2 promoter in ES cells. Using the CRISPR/Cas9 system and F1 ES cells ( Mus musculus 129 × Mus castaneus ), we generated heterozygous deletions of each enhancer region, revealing that only the distal cluster containing SRR107 and SRR111, located >100 kb downstream from Sox2 , is required for cis -regulation of Sox2 in ES cells. Furthermore, homozygous deletion of this distal Sox2 control region (SCR) caused significant reduction in Sox2 mRNA and protein levels, loss of ES cell colony morphology, genome-wide changes in gene expression, and impaired neuroectodermal formation upon spontaneous differentiation to embryoid bodies. Together, these data identify a distal control region essential for Sox2 transcription in ES cells.
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The SCR is a strong enhancer that accounts for most of the transcriptional activity of endogenous Sox2.
“The SCR is a strong enhancer that accounts for most of the transcriptional activity of endogenous Sox229,30.”
From Nonlinear control of transcription through enhancer–promoter interactions (2022) · cites this paper as [29]
The Results section, “The SCR is required for Sox2 transcription in ES cells” (page unavailable), reports an eightfold reduction in Sox2 mRNA from an allele after SCR deletion, supporting a major contribution to endogenous transcription in embryonic stem cells. The Discussion says the SCR may not be active in neural progenitor cells, so the unqualified claim extends beyond the cell type established by this study. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe truncated SCR contained only one of the two ~1.5 kb subregions that share similar transcription-factor-binding sites and independently operate as weaker enhancers of the Sox2 promoter in transient reporter assays.
“This contained only one of the two ~1.5 kb subregions that share similar transcription-factor-binding sites29 and independently operate as weaker enhancers of the Sox2 promoter in transient reporter assays29 (Extended Data Fig. 5b).”
From Nonlinear control of transcription through enhancer–promoter interactions (2022) · cites this paper as [29]
The Results section (‘Identification of transcriptional enhancers surrounding Sox2’; page unavailable) identifies SRR107 and SRR111 as independently active in luciferase reporter assays, with each weaker than the combined SCR. The Discussion reports that both bind the same listed transcription factors. Our copy does not establish that each subregion is approximately 1.5 kb or that the reporter assays specifically tested the Sox2 promoter; the statement about what the citing authors’ truncated SCR contained is their own framing. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSRR2 can drive modest activity in episomal reporter assays and is responsible for the ~10% residual expression of Sox2 that persists after removing the SCR.
“It can drive modest activity in episomal reporter assays (35, 45) and is responsible for the ~10% residual expression of Sox2 that persists after removing the SCR (Fig. 4F and fig. S26C).”
From Synergy between regulatory elements can render cohesin dispensable for distal enhancer function (2026) · cites this paper as [35]
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“Thus, the well-known SCR-Sox2 E–”
Influential
- Authors
- Zhou, H. Y., Katsman, Y., Dhaliwal, N. K., Davidson, S., Macpherson, N. N., Sakthidevi, M., Collura, F., & Mitchell, J. A.
- Affiliations
- University of Toronto (CA)
- Corresponding author
- Mitchell, Jennifer A.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2014-12-15
- Volume
- 28
- Issue
- 24
- Pages
- 2699-2711
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4265674
- OpenAlex
- W2102689239
- Cited by
- 192
- References
- 9
- Citations by year
- 2026: 17 · 2025: 14 · 2024: 17 · 2023: 22 · 2022: 14 · 2021: 17 · 2020: 18 · 2019: 22 · 2018: 13 · 2017: 10 · 2016: 16 · 2015: 12
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- Funders
- Ludwig Institute for Cancer Research
- Canadian Institutes of Health Research
- Ontario Ministry of Research and Innovation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- SOX2, embryonic stem cells, pluripotency, cis-regulation, enhancer deletion, chromatin looping, neuroectoderm differentiation, embryoid body differentiation, gene expression changes
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, Chromatin, Enhancer Elements, Genetic, Multigene Family, Promoter Regions, Genetic, Sequence Deletion, Gene Expression Regulation, Developmental, Mice, Embryonic Stem Cells, Neural Plate, SOXB1 Transcription Factors
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