Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells
Histone deacetylase (HDAC) 1 and 2 are essential for accurate cell division and the pluripotency of embryonic stem cells
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DOI：
10.1073/pnas.1321330111
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发表时间：
2014-07-08
影响因子：
11.1
通讯作者：
Cowley, Shaun M.
中科院分区：
文献类型：
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作者：
Jamaladdin, Shereen;Kelly, Richard D. W.;Cowley, Shaun M.
组蛋白去乙酰化酶1和2（HDAC 1/2）形成调节基因表达的辅阻遏物复合物的核心催化组分。在大多数细胞类型中，需要Hdac 1和Hdac 2两者的缺失来产生可辨别的表型，这表明它们的活性在很大程度上是冗余的。因此，我们已经产生了ES细胞系，其中Hdac 1和Hdac 2可以同时失活。HDAC 1/2的缺失导致总HDAC活性降低60%并导致细胞活力丧失。细胞死亡依赖于细胞周期进程，因为分化的非增殖细胞保持其活力。此外，我们观察到增加的有丝分裂缺陷，染色质桥，和微核，这表明HDAC 1/2是必要的准确的染色体分离。与基因表达调控中的关键作用一致，Hdac 1/2缺失细胞的微阵列分析揭示了1，708个差异表达基因。重要的是，对于维持干细胞自我更新，我们检测到多能转录因子Oct 4、Nanog、Esrrb和Rex 1的表达减少。HDAC 1/2活性通过夹在HDAC和其同源辅阻遏物之间的肌醇四磷酸分子（IP 4）的结合来调节。这就提出了一个重要的问题，即IP 4是否调节细胞中复合物的活性。通过挽救双敲除细胞的活力，我们首次证明（据我们所知），消除IP 4结合的突变降低了HDAC 1/2在体内的活性。我们的数据表明HDAC 1/2在细胞增殖中具有重要的多效性作用，并通过维持关键多能转录因子的表达来调节干细胞自我更新。
Histone deacetylases 1 and 2 (HDAC1/2) form the core catalytic components of corepressor complexes that modulate gene expression. In most cell types, deletion of both Hdac1 and Hdac2 is required to generate a discernible phenotype, suggesting their activity is largely redundant. We have therefore generated an ES cell line in which Hdac1 and Hdac2 can be inactivated simultaneously. Loss of HDAC1/2 resulted in a 60% reduction in total HDAC activity and a loss of cell viability. Cell death is dependent upon cell cycle progression, because differentiated, nonproliferating cells retain their viability. Furthermore, we observe increased mitotic defects, chromatin bridges, and micronuclei, suggesting HDAC1/2 are necessary for accurate chromosome segregation. Consistent with a critical role in the regulation of gene expression, microarray analysis of Hdac1/2-deleted cells reveals 1,708 differentially expressed genes. Significantly for the maintenance of stem cell self-renewal, we detected a reduction in the expression of the pluripotent transcription factors, Oct4, Nanog, Esrrb, and Rex1. HDAC1/2 activity is regulated through binding of an inositol tetraphosphate molecule (IP4) sandwiched between the HDAC and its cognate corepressor. This raises the important question of whether IP4 regulates the activity of the complex in cells. By rescuing the viability of double-knockout cells, we demonstrate for the first time (to our knowledge) that mutations that abolish IP4 binding reduce the activity of HDAC1/2 in vivo. Our data indicate that HDAC1/2 have essential and pleiotropic roles in cellular proliferation and regulate stem cell self-renewal by maintaining expression of key pluripotent transcription factors.