Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression
Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression
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DOI：
10.1101/gad.552310
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发表时间：
2010-03-01
影响因子：
10.5
通讯作者：
Matthias, Patrick
中科院分区：
文献类型：
--
作者：
Yamaguchi, Teppei;Cubizolles, Fabien;Matthias, Patrick
组蛋白脱乙酰酶（HDAC）通过使组蛋白脱乙酰化来调节基因表达，并且还调节许多非组蛋白蛋白的乙酰化，从而影响各种细胞过程。在这里，我们分析了主要的I类酶HDAC 1和HDAC 2在原代小鼠成纤维细胞和B细胞谱系。缺乏这两种酶的成纤维细胞不能在培养物中增殖，并在G1期表现出强烈的细胞周期阻滞，这与CDK抑制剂p21（WAF 1/CIP 1）和p57（Kip 2）以及相应mRNA的上调有关。这种调节是直接的，因为在野生型细胞中HDAC 1和HDAC 2与p21和p57基因的启动子区结合。此外，突变细胞中的转录组和组蛋白修饰的分析表明，HDAC 1和HDAC 2只有部分重叠的作用。接下来，我们消除了条件性靶向小鼠的B细胞中的HDAC 1和HDAC 2。我们发现，B细胞的发育严格要求这些酶中至少一种的存在：当这两种酶被消融时，B细胞发育在早期阶段被阻断，并且罕见的剩余前B细胞显示出G1期的阻断，伴随着细胞凋亡的诱导。相比之下，成熟静息B细胞中HDAC 1和HDAC 2的消除没有负面影响，除非这些细胞被诱导增殖。这些结果表明，HDAC 1和HDAC 2，通过正常抑制p21和p57的表达，调节细胞周期的G1期到S期的转变。
Histone deacetylases (HDACs) regulate gene expression by deacetylating histones and also modulate the acetylation of a number of nonhistone proteins, thus impinging on various cellular processes. Here, we analyzed the major class I enzymes HDAC1 and HDAC2 in primary mouse fibroblasts and in the B-cell lineage. Fibroblasts lacking both enzymes fail to proliferate in culture and exhibit a strong cell cycle block in the G1 phase that is associated with up-regulation of the CDK inhibitors p21(WAF1/CIP1) and p57(Kip2) and of the corresponding mRNAs. This regulation is direct, as in wild-type cells HDAC1 and HDAC2 are bound to the promoter regions of the p21 and p57 genes. Furthermore, analysis of the transcriptome and of histone modifications in mutant cells demonstrated that HDAC1 and HDAC2 have only partly overlapping roles. Next, we eliminated HDAC1 and HDAC2 in the B cells of conditionally targeted mice. We found that B-cell development strictly requires the presence of at least one of these enzymes: When both enzymes are ablated, B-cell development is blocked at an early stage, and the rare remaining pre-B cells show a block in G1 accompanied by the induction of apoptosis. In contrast, elimination of HDAC1 and HDAC2 in mature resting B cells has no negative impact, unless these cells are induced to proliferate. These results indicate that HDAC1 and HDAC2, by normally repressing the expression of p21 and p57, regulate the G1-to-S-phase transition of the cell cycle.