An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5.
An Embryonic Stem Cell-Specific NuRD Complex Functions through Interaction with WDR5.
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DOI：
10.1016/j.stemcr.2017.04.020
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发表时间：
2017-06-06
影响因子：
5.9
通讯作者：
Fazzio TG
中科院分区：
文献类型：
--
作者：
Ee LS;McCannell KN;Tang Y;Fernandes N;Hardy WR;Green MR;Chu F;Fazzio TG
核小体重塑和脱乙酰酶（NuRD）复合物是一种染色质调节复合物，在后生动物中作为转录辅阻遏物发挥作用。NuRD亚基MBD 3对于靶向和组装功能性NuRD复合物以及胚胎干细胞（ESC）多能性是必需的。三种MBD 3同种型（MBD 3A、MBD 3B和MBD 3C）在小鼠中表达。在这里，我们发现MBD 3C亚型含有一个独特的50个氨基酸的N-末端区域，这是MBD 3C特异性与组蛋白H3结合蛋白WDR 5相互作用所必需的。WDR 5的结构域分析揭示了H3结合口袋是与MBD 3C相互作用所必需的。我们发现，虽然Mbd 3c敲除ESC正常分化，但MBD 3C与MBD 3A和MBD 3B同种型在基因表达调控中是冗余的，这种冗余需要独特的MBD 3C N末端。总之，我们的数据表征了一种独特的NuRD复合物变体，该变体在ESC中特异性发挥作用。Mbd 3c通过其独特的N-末端结构域结合Wdr 5，Wdr 5相互作用对Mbd 3c功能至关重要Mbd 3c/NuRD可以替代ESC基因调控中的经典NuRD复合物Ee和同事表征了NuRD染色质重塑复合物的Mbd 3亚基的胚胎干细胞（ESC）特异性同种型。这种称为Mbd 3c的变体形成了一种变体NuRD复合物，该复合物包含组蛋白结合蛋白Wdr 5，这种相互作用对其在基因调控中的功能至关重要。Mbd 3c/NuRD或典型NuRD复合物（含有Mbd 3a或Mbd 3b同种型）的存在对于正常基因调控和ESC多能性是必需的。
The Nucleosome Remodeling and Deacetylase (NuRD) complex is a chromatin regulatory complex that functions as a transcriptional co-repressor in metazoans. The NuRD subunit MBD3 is essential for targeting and assembly of a functional NuRD complex as well as embryonic stem cell (ESC) pluripotency. Three MBD3 isoforms (MBD3A, MBD3B, and MBD3C) are expressed in mouse. Here, we find that the MBD3C isoform contains a unique 50-amino-acid N-terminal region that is necessary for MBD3C to specifically interact with the histone H3 binding protein WDR5. Domain analyses of WDR5 reveal that the H3 binding pocket is required for interaction with MBD3C. We find that while Mbd3c knockout ESCs differentiate normally, MBD3C is redundant with the MBD3A and MBD3B isoforms in regulation of gene expression, with the unique MBD3C N terminus required for this redundancy. Together, our data characterize a unique NuRD complex variant that functions specifically in ESCs. Mbd3c binds Wdr5 through its unique N-terminal domain Wdr5 interaction is critical for Mbd3c function Mbd3c/NuRD can substitute for canonical NuRD complex in ESC gene regulation Ee and colleagues characterize an embryonic stem cell (ESC)-specific isoform of the Mbd3 subunit of the NuRD chromatin remodeling complex. This variant, called Mbd3c, forms a variant NuRD complex that incorporates the histone binding protein Wdr5, and this interaction is critical for its functions in gene regulation. The presence of either Mbd3c/NuRD or canonical NuRD complex (containing either the Mbd3a or Mbd3b isoform) is necessary for normal gene regulation and ESC pluripotency.