The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure
The MiDAC histone deacetylase complex is essential for embryonic development and has a unique multivalent structure
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DOI：
10.1038/s41467-020-17078-8
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发表时间：
2020-06-26
影响因子：
16.6
通讯作者：
Schwabe, John W. R.
中科院分区：
文献类型：
--
作者：
Turnbull, Robert E.;Fairall, Louise;Schwabe, John W. R.
MiDAC是七种不同的大型多蛋白复合物之一，其将I类组蛋白脱乙酰酶募集到基因组中以调节基因表达。尽管涉及细胞周期调控和几种癌症，但令人惊讶的是，对MiDAC的功能或结构知之甚少。在这里，我们表明，MiDAC在癌细胞系有丝分裂过程中对染色体对齐很重要。缺乏MiDAC蛋白、DNTTIP1或MIDEAS的小鼠在胚胎发育后期由于基因表达的扰动而以相同的表型死亡，从而导致心脏畸形和造血功能衰竭。这表明MiDAC具有其他HDAC复合物无法补偿的基本和独特功能。与此一致，MiDAC的cryoEM结构揭示了独特的组装模式。HDAC1的四个拷贝位于外周，具有面向外的活性位点，这表明该复合物可能靶向多个核小体，这意味着进行性脱乙酰酶功能。MiDAC复合物将I类组蛋白脱乙酰酶招募到染色质，但对其精确结构和功能知之甚少。在这里，作者探讨了MiDAC在细胞周期和小鼠胚胎发生过程中的作用，并提出了cryoEM结构，以深入了解MiDAC的组装模式。
MiDAC is one of seven distinct, large multi-protein complexes that recruit class I histone deacetylases to the genome to regulate gene expression. Despite implications of involvement in cell cycle regulation and in several cancers, surprisingly little is known about the function or structure of MiDAC. Here we show that MiDAC is important for chromosome alignment during mitosis in cancer cell lines. Mice lacking the MiDAC proteins, DNTTIP1 or MIDEAS, die with identical phenotypes during late embryogenesis due to perturbations in gene expression that result in heart malformation and haematopoietic failure. This suggests that MiDAC has an essential and unique function that cannot be compensated by other HDAC complexes. Consistent with this, the cryoEM structure of MiDAC reveals a unique and distinctive mode of assembly. Four copies of HDAC1 are positioned at the periphery with outward-facing active sites suggesting that the complex may target multiple nucleosomes implying a processive deacetylase function. The MiDAC complex recruits class I histone deacetylases to chromatin but little is known about its precise structure and function. Here, the authors explore the role of MiDAC in the cell cycle and during mouse embryogenesis, and present cryoEM structures that provide insight into MiDAC's mode of assembly.