The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis.
The chromatin-targeting protein Brd2 is required for neural tube closure and embryogenesis.
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DOI：
10.1016/j.bbagrm.2009.03.005
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发表时间：
2009-05
期刊：
影响因子：
--
通讯作者：
Freiman RN
中科院分区：
文献类型：
--
作者：
Gyuris A;Donovan DJ;Seymour KA;Lovasco LA;Smilowitz NR;Halperin AL;Klysik JE;Freiman RN
染色质修饰对于在胚胎发育期间指导转录是必不可少的。含溴结构域蛋白2（Brd 2;也称为RING 3和Fsrg 1）是已知选择性结合乙酰化组蛋白H3和H4的四个BET（溴结构域和额外末端结构域）家族成员之一。Brd 2与包括介体、TFIID和Swi/Snf多蛋白复合物的转录装置的多个亚基相关联。虽然Brd 2的分子相互作用是已知的，但Brd 2在哺乳动物胚胎发生中的功能仍然未知。在开发Brd 2缺陷的小鼠模型中，我们发现Brd 2是完成胚胎发生和发育过程中适当的神经管闭合所必需的。缺乏Brd 2表达的胚胎可存活至胚胎第13.5天，即妊娠中期后不久，并显示出完全渗透性神经形成缺陷，这在很大程度上导致发育中的后脑露脑。在这项研究中，我们发现，最高的Brd 2的表达是在发育中的神经管，与神经管缺陷发现Brd 2-null胚胎。此外，缺乏Brd 2表达的胚胎显示改变的基因表达程序，包括已知指导神经元发育的多个基因的错误表达。总之，这些结果暗示Brd 2作为哺乳动物胚胎发生和神经发生过程中染色质结构和转录的关键整合剂的重要作用。
Chromatin modifications are essential for directing transcription during embryonic development. Bromodomain-containing protein 2 (Brd2; also called RING3 and Fsrg1) is one of four BET (bromodomain and extra terminal domain) family members known to selectively bind acetylated histones H3 and H4. Brd2 associates with multiple subunits of the transcriptional apparatus including the mediator, TFIID and Swi/Snf multi-protein complexes. While molecular interactions of Brd2 are known, the functions of Brd2 in mammalian embryogenesis remain unknown. In developing a mouse model deficient in Brd2, we find that Brd2 is required for the completion of embryogenesis and proper neural tube closure during development. Embryos lacking Brd2 expression survive up to embryonic day 13.5, soon after mid-gestation, and display fully penetrant neurulation defects that largely result in exencephaly of the developing hindbrain. In this study, we find that highest expression of Brd2 is detected in the developing neural tube, correlating with the neural tube defects found in Brd2-null embryos. Additionally, embryos lacking Brd2 expression display altered gene expression programs, including the mis-expression of multiple genes known to guide neuronal development. Together these results implicate essential roles for Brd2 as a critical integrator of chromatin structure and transcription during mammalian embryogenesis and neurogenesis.
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