The function of chromatin modifiers in lineage commitment and cell fate specification.
The function of chromatin modifiers in lineage commitment and cell fate specification.
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DOI：
10.1111/febs.13132
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Hendrich B
中科院分区：
文献类型：
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作者：
Signolet J;Hendrich B
已知，改变染色质结构的蛋白质对后生动物生物学的各个方面都很重要，包括发育、疾病和可能的衰老。然而，这些蛋白质为什么重要，即它们的作用如何影响给定的生物过程，缺乏功能细节。虽然现在可以描述这些蛋白质如何重塑染色质，它们在细胞系中的染色质结合谱，或特定蛋白质丢失后基因表达的变化的生物化学，但在极少数情况下，这很容易转化为对该蛋白质的功能如何实际影响发育过程的理解。鉴于许多染色质修饰蛋白将在很大程度上通过控制基因表达来发挥其影响，将发育过程视为基因调控网络(GRN)的变化是有用的，每种细胞类型都表现出独特的基因表达谱。在本文中，我们考虑了两个丰富且高度保守的染色质修饰复合体，即核小体重塑和脱乙酰化(NuRD)复合体和多梳抑制复合体2(PRC2)，它们对哺乳动物早期发育过程中与血统承诺相关的GRN的变化产生了影响。我们认为，虽然NuRD复合体限制了细胞状态的稳定性，并定义了两个稳定状态之间的发展轨迹，但PRC2的活性对于稳定一个新的GRN是重要的。虽然这两个复合体显示出不同的生化活性、染色质结合谱和突变表型，但我们提出了一个模型来解释它们如何合作以促进细胞状态的转变，即发育。
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 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 remodelling 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. Although 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.