The function of chromatin modifiers in lineage commitment and cell fate specification
The FEBS Journal
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Signolet, J., & Hendrich, B. (2014). The function of chromatin modifiers in lineage commitment and cell fate specification. The FEBS Journal, 282 1692-1702. https://doi.org/10.1111/febs.13132
Proteins that modify the structure of chromatin are known to be important for various aspects of metazoan biology including development, disease, and possibly ageing. Yet functional details of why these proteins are important, i.e. how their action influences a given biological process, are lacking. While it is now possible to describe the biochemistry of how these proteins remodel chromatin, their chromatin binding profiles in cell lines, or to describe gene expression changes upon loss of a given protein, in very few cases has this easily translated into an understanding of how the function of that protein actually influences a developmental process. Given that many chromatin modifying proteins will largely exert their influence through control of gene expression, it is useful to consider developmental processes as changes in the gene regulatory network (GRN), with each cell type exhibiting a unique gene expression profile. In this essay we consider the impact of two abundant and highly conserved chromatin modifying complexes, namely the Nucleosome Remodeling and Deacetylation (NuRD) complex and the Polycomb Repressive Complex 2 (PRC2), on the change in GRNs associated with lineage commitment during early mammalian development. We propose that while the NuRD complex limits the stability of cell states and defines the developmental trajectory between two stable states, PRC2 activity is important for stabilizing a new GRN once established. Though these two complexes display different biochemical activities, chromatin binding profiles and mutant phenotypes, we propose a model to explain how they cooperate to facilitate the transition through cell states that is development.
Work in the BH Lab is supported by a Wellcome Trust Senior Research Fellowship in the Basic Biomedical Sciences held by BH, and by the Wellcome Trust – Medical Research Council Stem Cell Institute. JS was funded as a PhD student by the UK Medical Research Council during part of this work.
Wellcome Trust (098021/Z/11/Z)
External DOI: https://doi.org/10.1111/febs.13132
This record's URL: https://www.repository.cam.ac.uk/handle/1810/246289