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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation
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Histone deacetylase 1 (HDAC1), but not HDAC2, controls embryonic stem cell differentiation

机译：组蛋白脱乙酰基酶1（HDAC1），而非HDAC2，控制胚胎干细胞分化

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摘要

Histone deacetylases (HDAC) 1 and 2 are highly similar enzymes that help regulate chromatin structure as the core catalytic components of corepressor complexes. Although tissue-specific deletion of HDAC1 and HDAC2 has demonstrated functional redundancy, germ-line deletion of HDAC1 in the mouse causes early embryonic lethality, whereas HDAC2 does not. To address the unique requirement for HDAC1 in early embryogenesis we have generated conditional knockout embryonic stem (ES) cells in which HDAC1 or HDAC2 genes can be inactivated. Deletion of HDAC1, but not HDAC2, causes a significant reduction in the HDAC activity of Sin3A, NuRD, and CoREST corepressor complexes. This reduced corepressor activity results in a specific 1.6-fold increase in histone H3 K56 acetylation (H3K56Ac), thus providing genetic evidence that H3K56AC is a substrate of HDAC1. In culture, ES cell proliferation was unaffected by loss of either HDAC1 or HDAC2. Rather, we find that loss of HDAC1 affects ES cell differentiation. ES cells lacking either HDAC1 or HDAC2 were capable of forming embryoid bodies (EBs), which stimulates differentiation into the three primary germ layers. However, HDACI-deficient EBs were significantly smaller, showed spontaneous rhythmic contraction, and increased expression of both cardiomyocyte and neuronal markers. In summary, our genetic study of HDAC1 and HDAC2 in ES cells, which mimic the embryonic epiblast, has identified a unique requirement for HDAC1 in the optimal activity of HDAC1/2 corepressor complexes and cell fate determination during differentiation.
机译：组蛋白脱乙酰基酶（HDAC）1和2是高度相似的酶，有助于调节染色质的结构，作为共抑物复合物的核心催化成分。尽管HDAC1和HDAC2的组织特异性缺失已显示出功能冗余，但是小鼠中HDAC1的种系缺失会导致早期胚胎致死，而HDAC2不会。为了满足早期胚胎发生过程中对HDAC1的独特需求，我们生成了条件敲除胚胎干（ES）细胞，其中HDAC1或HDAC2基因可以被灭活。删除HDAC1（而不是HDAC2）会导致Sin3A，NuRD和CoREST核心加压复合物的HDAC活性大大降低。这种降低的抗核心蛋白活性导致组蛋白H3 K56乙酰化（H3K56Ac）特异性增加1.6倍，从而提供了遗传学证据证明H3K56AC是HDAC1的底物。在培养中，ES细胞增殖不受HDAC1或HDAC2丢失的影响。相反，我们发现HDAC1的缺失会影响ES细胞的分化。缺少HDAC1或HDAC2的ES细胞能够形成胚状体（EB），从而刺激分化为三个主要细菌层。但是，缺乏HDACI的EB明显较小，表现出自发的节律性收缩，并且心肌细胞和神经元标志物的表达均增加。总而言之，我们对ES细胞中HDAC1和HDAC2的遗传研究（模仿了胚胎上皮细胞）已经确定了HDAC1 / 2在HDAC1 / 2核心抑制剂复合物的最佳活性和分化过程中细胞命运确定方面的独特要求。

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