Mof-associated complexes have overlapping and unique roles in regulating pluripotency in embryonic stem cells and during differentiation

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.Embryonic stem cells are special cells that have the ability to become many different types of cells, such as skin, muscle, or neuronal cells. This process is called differentiation. They can also undergo a process called self-renewal to produce more embryonic stem cells. These processes are controlled by a complex network of enzymes, and the production of these enzymes depends on various genes within the organism being expressed as proteins.The DNA that holds the genetic information inside cells spends most of its time wrapped around proteins called histones: this allows the DNA molecules—which can be up to several metres long in some species—to fit inside the cell nucleus; it also protects the DNA molecules, which are quite fragile, from damage. Enzymes that attach chemical groups called acetyl groups to histones have a central role in controlling the self-renewal and differentiation of embryonic stem cells.Mof is an enzyme that attaches an acetyl group to a specific position in a particular histone. It is a subunit within two larger protein complexes that were originally identified in flies: the male-specific lethal (MSL) complex, which is only found in male flies, and the non-specific lethal (NSL) complex, which is found in both male and female flies. These complexes have been widely studied in flies, and the role of the Mof enzyme is also reasonably well understood in mammals. However, the roles of the MSL and NSL protein complexes in mammals are not fully understood.Ravens et al. have now used a combination of a technique called ChIP-seq (which can identify binding sites anywhere in the genome) and genetic ‘knock down’ experiments to explore the roles of these two complexes in mouse embryonic stem cells and neuronal progenitor cells.There is some overlap between the genes that the complexes act on. However, NSL acts on some genes than MSL does not act on, and vice versa. NSL mostly acts on genes that have ‘housekeeping’ functions and are expressed in many different cell types. MSL binds more to genes that are specific to embryonic stem cells, and acts on genes required for the development of neuronal progenitor cells. This means that NSL regulates the growth of embryonic stem cells, whereas MSL controls their development and differentiation.