A developmentally regulated long-range enhancer-promoter contact mediates human neural development
SOX2 is a core pluripotency factor in human embryonic stem cells (hESCs), but upon differentiation to the three germ layers, its expression is preserved selectively in neuroectoderm. The mechanisms regulating <i>SOX2</i> transcription in distinct developmental stages remain incompletely understood. Here, we demonstrate that a distant enhancer 550 kb from the human <i>SOX2</i> locus is selectively activated in neural stem cells (NSCs) and establishes long-range contact with the <i>SOX2</i> gene. CRISPR-Cas9 excision of the enhancer has no effect in hESCs but reduces <i>SOX2</i> transcription in NSCs and impairs neuroectodermal differentiation and forebrain specification in teratomas and cerebral organoids. CRISPR excision of a CTCF recognition motif adjacent to the enhancer does not affect enhancer activation in neuroectoderm but reduces chromatin looping and <i>SOX2</i> transcription to partially reproduce phenotypes seen with enhancer deletion. Our findings indicate that the development of the human nervous system depends on a developmentally regulated long-range contact between a distant enhancer and the <i>SOX2</i> locus.
Authors
- Sara Haddock (ORCID: https://orcid.org/0000-0002-5661-5317)
- Priscillia Lhoumaud
- Kristyn Galbraith (ORCID: https://orcid.org/0000-0002-5660-866X)
- Finnegan Clark (ORCID: https://orcid.org/0000-0003-0575-7312)
- C. Kim
- Ángel Luis Guerrero Peral (ORCID: https://orcid.org/0000-0001-7493-6002)
- Niklas Ravn-Boess (ORCID: https://orcid.org/0000-0001-6525-5942)
- Aristotelis Tsirigos (ORCID: https://orcid.org/0000-0002-7512-8477)
- Joshua D. Frenster (ORCID: https://orcid.org/0000-0003-2401-1575)
- Timothée Lionnet (ORCID: https://orcid.org/0000-0003-1508-0202)
- Dimitris G. Placantonakis (ORCID: https://orcid.org/0000-0003-1950-2978)
- Jod Prado
- Matija Snuderl (ORCID: https://orcid.org/0000-0003-0752-0917)
- Devin Bready (ORCID: https://orcid.org/0000-0003-3557-2888)
- Jane A. Skok (ORCID: https://orcid.org/0000-0002-4145-1516)
- Jonathan Sabio (ORCID: https://orcid.org/0009-0002-1138-7493)
- Catherine Do (ORCID: https://orcid.org/0000-0002-9796-4345)
- Shuai Wang (ORCID: https://orcid.org/0000-0002-9252-7496)
- Albert Xin Jiang
- Cathryn Lapierre
- Robert Kushmakov
Institutions
- NYU Langone Health (US)
- New York University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-03
- DOI
- https://doi.org/10.64898/2025.12.01.691702
- Primary Topic
- Pluripotent Stem Cells Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00