Friedrich Miescher Institute for Biomedical Research, Novartis Research Foundation, Basel, Switzerland.
Genes Dev. 2010 Mar 1;24(5):455-69. doi: 10.1101/gad.552310.
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.
组蛋白去乙酰化酶（HDACs）通过去乙酰化组蛋白来调节基因表达，还调节许多非组蛋白的乙酰化，从而影响各种细胞过程。在这里，我们分析了主要的 I 类酶 HDAC1 和 HDAC2 在原代小鼠成纤维细胞和 B 细胞系中的作用。缺乏这两种酶的成纤维细胞在培养中无法增殖，并在 G1 期出现强烈的细胞周期阻滞，这与 CDK 抑制剂 p21（WAF1/CIP1）和 p57（Kip2）的上调及其相应的 mRNA 有关。这种调节是直接的，因为在野生型细胞中，HDAC1 和 HDAC2 与 p21 和 p57 基因的启动子区域结合。此外，对突变细胞的转录组和组蛋白修饰分析表明，HDAC1 和 HDAC2 具有部分重叠的作用。接下来，我们在条件性靶向小鼠的 B 细胞中消除了 HDAC1 和 HDAC2。我们发现 B 细胞的发育严格需要至少有一种酶的存在：当两种酶都被消除时，B 细胞的发育在早期被阻断，而罕见的剩余前 B 细胞在 G1 期出现阻滞，伴随着细胞凋亡的诱导。相比之下，在成熟静止的 B 细胞中消除 HDAC1 和 HDAC2 没有负面影响，除非这些细胞被诱导增殖。这些结果表明，HDAC1 和 HDAC2 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。
