Enhancer decommissioning by LSD1 during embryonic stem cell differentiation

By Warren A. Whyte, S. Bilodeau, David A. Orlando, Heather A. Hoke, G. Frampton, Charles T. Foster, S. Cowley, Richard A. Young. Nature, 2012

599 citations recorded by the source corpus.

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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b9f0b547cf95e1f7d16e28bd531e4c90a462393d

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Citations in the corpus

Systematic discovery of Xist RNA binding proteins (2015, background): “NuRD complex decommissions ESC enhancers to enable differentiation and lineage commitment—the same developmental window where XCI takes place (Reynolds et al., 2012; Whyte et al., 2012).”
Master Transcription Factors and Mediator Establish Super-Enhancers at Key Cell Identity Genes (2013, unknown): “(EPUs), and genome-wide interactions discovered by chromosome conformation capture techniques (Dixon et al., 2012; Shen et al., 2012; Whyte et al., 2012).”
Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes (2014, unknown): “5 murine ESCs were grown on irradiated murine embryonic fibroblasts (MEFs) under standard ESC conditions as described previously (Whyte et al., 2012).”
Modification of enhancer chromatin: what, how and why? (2013, background): “Ultimately, histone H3K4me1 is lost or reduced at enhancers after they become disengaged or ‘‘decommissioned’’ after departure of TFs and Pol II; at least during ESC differentiation, this process is mediated through demethylation by LSD1 (Whyte et al., 2012).”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, unknown): “, 2007), DNase I hypersensitivity site (modENCODE project), and binding sites of pluripotency TFs (Whyte et al., 2012).”
Remodeling of the enhancer landscape during macrophage activation is coupled to enhancer transcription (2013, background): “Studies indicate that LSD1 directly binds to and is required for the ‘‘decommissioning’’ of embyonic stem cell-specific enhancers during ES cell differentiation by removing the H3K4me1/2 marks (Whyte et al., 2012).”
The LSD1 Family of Histone Demethylases and the Pumilio Posttranscriptional Repressor Function in a Complex Regulatory Feedback Loop (2015, background): “Another possibility would be that LSD1 catalytic activity at these genes is blocked by specific cofactors or by the presence of acetylated histones, as previously observed in embryonic stem cells (12).”
Super-enhancers in the control of cell identity and disease. (2013, unknown): “N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript differentiation (Denslow and Wade, 2007; Foster et al., 2010; Kaji et al., 2006; Kaji et al., 2007; Reynolds et al., 2012a; Reynolds et al., 2012b; Shi et al., 2004; Whyte et al., 2012).”