Enhancer decommissioning by LSD1 during embryonic stem cell differentiation
Open accessAbstract
Transcription factors and chromatin modifiers are important in the programming and reprogramming of cellular states during development. Transcription factors bind to enhancer elements and recruit coactivators and chromatin-modifying enzymes to facilitate transcription initiation. During differentiation a subset of these enhancers must be silenced, but the mechanisms underlying enhancer silencing are poorly understood. Here we show that the histone demethylase lysine-specific demethylase 1 (LSD1; ref. 5), which demethylates histone H3 on Lys 4 or Lys 9 (H3K4/K9), is essential in decommissioning enhancers during the differentiation of mouse embryonic stem cells (ESCs). LSD1 occupies enhancers of active genes that are critical for control of the state of ESCs. However, LSD1 is not essential for the maintenance of ESC identity. Instead, ESCs lacking LSD1 activity fail to differentiate fully, and ESC-specific enhancers fail to undergo the histone demethylation events associated with differentiation. At active enhancers, LSD1 is a component of the NuRD (nucleosome remodelling and histone deacetylase) complex, which contains additional subunits that are necessary for ESC differentiation. We propose that the LSD1-NuRD complex decommissions enhancers of the pluripotency program during differentiation, which is essential for the complete shutdown of the ESC gene expression program and the transition to new cell states.
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LSD1 suppresses thousands of enhancers in ES cells.
“LSD1, a histone demethylase that has been shown previously to suppress active enhancers during embryonic stem (ES) cell differentiation (Whyte et al., 2012)”
From The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer (2015) · cites this paper as Whyte et al., 2012
HDAC1/2 themselves and their related complex components Sin3A and LSD1 all map within the vicinity of transcriptional start sites.
“This is perhaps unsurprising since HDAC1/2 themselves (Fig. 4C) and their related complex components, Sin3A37 and LSD138, all map within the vicinity of TSS.”
From Histone deacetylase (HDAC) 1 and 2 complexes regulate both histone acetylation and crotonylation in vivo (2018) · cites this paper as [38]
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- Authors
- Whyte, W. A., Bilodeau, S., Orlando, D. A., Hoke, H. A., Frampton, G. M., Foster, C. T., Cowley, S. M., & Young, R. A.
- Affiliations
- Whitehead Institute for Biomedical Research (US)
- University of Leicester (GB)
- Corresponding author
- Young, Richard A.
- Venue
- Nature
- Published
- 2012-02-01
- Volume
- 482
- Issue
- 7384
- Pages
- 221-225
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC4144424
- OpenAlex
- W2013785611
- Cited by
- 602
- References
- 30
- Citations by year
- 2026: 12 · 2025: 22 · 2024: 34 · 2023: 33 · 2022: 29 · 2021: 36 · 2020: 56 · 2019: 46 · 2018: 41 · 2017: 50 · 2016: 48 · 2015: 49 · 2014: 58 · 2013: 54 · 2012: 34
- FWCI
- 25.09
- Type
- journal article
- Language
- en
- Update notices
- correction (2018-09-12)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Leicester Research Archive (University of Leicester) (submittedVersion)
- Funders
- Canadian Institutes of Health Research
- Medical Research Council (MR/J009202/1)
- National Human Genome Research Institute (HG002668, R01HG002668)
- National Institute of Neurological Disorders and Stroke (NS055923, P01NS055923)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- LSD1, NuRD complex, histone demethylation, embryonic stem cell differentiation, pluripotency, chromatin regulation, gene silencing, mouse embryonic stem cells
- MeSH terms
- Animals, Cell Differentiation, Enhancer Elements, Genetic, Fibroblasts, Oxidoreductases, N-Demethylating, Promoter Regions, Genetic, Gene Silencing, Mice, Embryonic Stem Cells, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Histone Demethylases
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