Abstract
The histone acetyltransferase (HAT) Mof is essential for mouse embryonic stem cell (mESC) pluripotency and early development. Mof is the enzymatic subunit of two different HAT complexes, MSL and NSL. The individual contribution of MSL and NSL to transcription regulation in mESCs is not well understood. Our genome-wide analysis show that i) MSL and NSL bind to specific and common sets of expressed genes, ii) NSL binds exclusively at promoters, iii) while MSL binds in gene bodies. Nsl1 regulates proliferation and cellular homeostasis of mESCs. MSL is the main HAT acetylating H4K16 in mESCs, is enriched at many mESC-specific and bivalent genes. MSL is important to keep a subset of bivalent genes silent in mESCs, while developmental genes require MSL for expression during differentiation. Thus, NSL and MSL HAT complexes differentially regulate specific sets of expressed genes in mESCs and during differentiation.
Highlights
Pluripotent mouse embryonic stem cells have the ability to self-renew or to differentiate into all cell types
Gel filtration followed by western blot analyses further indicated that Msl1 and Nsl1 are only present in Mof-containing complexes as they have eluted from the Superose 6 column in the same molecular weight containing fractions as their respective entire endogenous malespecific lethal (MSL), or non-specific lethal (NSL) complexes (Figure 1D)
These results together demonstrate the incorporation of all nuclear Msl1, or Nsl1, together with Mof, in their respective endogenous complexes and a fraction of ‘free’ Mof that is not present in either MSL or NSL
Summary
Pluripotent mouse embryonic stem cells (mESCs) have the ability to self-renew or to differentiate into all cell types. Chromatinmodifying enzymes further regulate transcriptional mESCs networks and cellular differentiation processes and can be associated with activation or repression of genes (Orkin and Hochedlinger, 2011). Histone acetylation is important for mESC pluripotency and is regulated by the concerted action of histone acetyltransferases (HATs) and histone deacetylases (HDACs) (Meshorer and Misteli, 2006). Acetylation of histone proteins leads to an open and dynamic chromatin conformation allowing an active transcription state, which is a signature of mESC pluripotency (Meshorer, 2007; Niwa, 2007; Efroni et al, 2008). In line with the requirement of histone acetylation in mESC maintenance and differentiation, genetic deletion or knockdown of several HATs affects mESC pluripotency (Lin et al, 2007; Fazzio et al, 2008; Gupta et al, 2008; Thomas et al, 2008; Zhong and Jin, 2009; Li et al, 2012)
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