Enhancer Decommissioning by LSD1 during Embryonic Stem Cell Differentiation



Enhancer decommissioning by LSD1 during embryonic stem cell differentiation

Introduction

LSD1 was known to be critical to development, but little was known about the key role it plays during differentiation, when operating systems are switched. 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. (Kagey . et al 2010). Kagey. et al (2010) proposed 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.

Synthesis

By investigating gene silencing during cell state transitions, Bilodeau and Warren Whyte, a Young lab graduate student and co-author of the Nature paper, redefined LSD1's role and described a previously unknown mechanism for silencing genes. (Pardo et al. 2010)

When they looked at the embryonic stem cell operating system genes that must be turned off during differentiation, Whyte and Bilodeau found LSD1 poised on the stem cell genes' enhancers, short bits of DNA that act as a landing pad for the proteins that enhance a gene's transcription and ultimately its protein production. When LSD1 receives the signal that the stem cell is transitioning into a more differentiated state, the enzyme pops into action and silences the ESC genes' enhancers. With their enhancers no longer operational, transcription of the stem cell genes is silenced, shutting down the stem cell operating system. As this occurs, other mechanisms switch on the cell's new operating system.

In fig. 1 of the article the results revealed that LSD1 occupies the enhancers and core promoters of a substantial population of actively transcribed and bivalent genes. Inspection of individual gene tracks showed that LSD1 occupies well-characterized enhancer regions together with the ESC master transcription factors Oct4, Sox2 and Nanog and the Mediator coactivator. A global view of enhancer regions occupied by Oct4, Sox2, Nanog and Mediator confirmed that 97% of the 3,838 high-confidence enhancers were also occupied by LSD1 (P,1029) This is consistent with evidence that LSD1 can interact with Oct4. LSD1 signals were also observed at core promoter regions with RNA polymerase II (Pol II) and TATA-Binding Protein (TBP) ; Fig. 1d). The TATA-binding protein (TBP) is a general transcription factor that binds specifically to a DNA sequence called the TATA box. The density of LSD1 signals at enhancers was higher than at core promoters(; Supplementary Fig. 1), indicating that LSD1 is associated predominantly with the enhancers of actively transcribed genes in ESCs. (Chen et al, 2008)

In fig. 2 of the article, loss of Oct4 expression led to a rapid loss of ESC morphology and a marked decrease in the levels of SSEA-1 and alkaline phosphatase, two markers of ESCs. When these ESCs were treated with ...