Distinct CoREST complexes act in a cell-type-specific manner
Distinct CoREST complexes act in a cell-type-specific manner
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DOI：
10.1093/nar/gkz1050
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发表时间：
2019-12-16
影响因子：
14.9
通讯作者：
Brehm, Alexander
中科院分区：
文献类型：
--
作者：
Macinkovic, Igor;Theofel, Ina;Brehm, Alexander
Corest已被确定为几个蛋白质复合体的一个亚单位，在发育过程中会产生转录抑制的染色质结构。然而，还没有对岩心相互作用组进行全面的分析。我们用蛋白质组学的方法确定了果蝇中两种dCoREST亚型，dCoREST-L和dCoREST-M的相互作用。我们确定了三个围绕共同的dCoREST/dRPD3核心构建的不同的组蛋白脱乙酰酶复合体：dLSD1/dCoREST复合体、lint复合体和dG9a/dCoREST复合体。后两种复合体可以结合两种dCoREST异构体。相反，dLSD1/dCoREST复合体只与dCoREST-L亚型组装。全基因组研究表明，这三个dCoREST复合体主要与染色质结合在启动子上。对S2细胞和睾丸的转录组分析表明，不同的细胞系利用不同的dCoREST复合体来维持细胞类型特异性的基因表达程序：在巨噬细胞样的S2细胞中，lint抑制与生殖系相关的基因，而其他dCoREST复合体在很大程度上是必不可少的。相比之下，在睾丸中，dLSD1/dCoREST复合体阻止了不适合生殖系的基因的转录，对于精子发生和生育是必不可少的，而其他dCoREST复合体的耗尽则没有影响。我们的研究发现了三个不同的dCoREST复合体，它们以血统受限的方式发挥作用，抑制特定的基因集，从而维持细胞类型特定的基因表达程序。
CoREST has been identified as a subunit of several protein complexes that generate transcriptionally repressive chromatin structures during development. However, a comprehensive analysis of the CoREST interactome has not been carried out. We use proteomic approaches to define the interactomes of two dCoREST isoforms, dCoREST-L and dCoREST-M, in Drosophila. We identify three distinct histone deacetylase complexes built around a common dCoREST/dRPD3 core: A dLSD1/dCoREST complex, the LINT complex and a dG9a/dCoREST complex. The latter two complexes can incorporate both dCoREST isoforms. By contrast, the dLSD1/dCoREST complex exclusively assembles with the dCoREST-L isoform. Genome-wide studies show that the three dCoREST complexes associate with chromatin predominantly at promoters. Transcriptome analyses in S2 cells and testes reveal that different cell lineages utilize distinct dCoREST complexes to maintain cell-type-specific gene expression programmes: In macrophage-like S2 cells, LINT represses germ line-related genes whereas other dCoREST complexes are largely dispensable. By contrast, in testes, the dLSD1/dCoREST complex prevents transcription of germ line-inappropriate genes and is essential for spermatogenesis and fertility, whereas depletion of other dCoREST complexes has no effect. Our study uncovers three distinct dCoREST complexes that function in a lineage-restricted fashion to repress specific sets of genes thereby maintaining cell-type-specific gene expression programmes.