HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development
HBO1 Is Required for H3K14 Acetylation and Normal Transcriptional Activity during Embryonic Development
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DOI：
10.1128/mcb.00159-10
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发表时间：
2011-02-01
影响因子：
5.3
通讯作者：
Thomas, Tim
中科院分区：
文献类型：
--
作者：
Kueh, Andrew J.;Dixon, Mathew P.;Thomas, Tim
我们在这里报道了Myst组蛋白乙酰转移酶HBO1(与ORC结合的组蛋白乙酰转移酶；MYST2/KAT7)是哺乳动物原肠后发育所必需的。缺乏HBO1导致组蛋白3赖氨酸14(H3K14)乙酰化减少90%以上，而在其他组蛋白残基上没有检测到乙酰化减少。H3K14乙酰化水平的降低伴随着所研究的大多数基因表达的下降。然而，一些基因，特别是调控胚胎模式的基因，受到的影响比“管家”基因更严重。HBO1缺乏的胚胎发育受阻于10体节体期。血管、间充质和体节排列紊乱。与以前报道的HBO1缺失培养细胞的细胞周期停滞不同，Hbo1突变胚胎原代成纤维细胞或永生化成纤维细胞没有发现DNA复制或细胞增殖缺陷。相反，在Hbo1突变胚胎中观察到高比例的细胞死亡和DNA片段化，最初导致间充质组织退化，最终导致胚胎死亡。总之，HBO1在发育中的主要作用是转录激活因子，这对于H3K14乙酰化和调节胚胎发育的必要基因的正常表达是不可或缺的。
We report here that the MYST histone acetyltransferase HBO1 (histone acetyltransferase bound to ORC; MYST2/KAT7) is essential for postgastrulation mammalian development. Lack of HBO1 led to a more than 90% reduction of histone 3 lysine 14 (H3K14) acetylation, whereas no reduction of acetylation was detected at other histone residues. The decrease in H3K14 acetylation was accompanied by a decrease in expression of the majority of genes studied. However, some genes, in particular genes regulating embryonic patterning, were more severely affected than "housekeeping" genes. Development of HBO1-deficient embryos was arrested at the 10-somite stage. Blood vessels, mesenchyme, and somites were disorganized. In contrast to previous studies that reported cell cycle arrest in HBO1-depleted cultured cells, no defects in DNA replication or cell proliferation were seen in Hbo1 mutant embryo primary fibroblasts or immortalized fibroblasts. Rather, a high rate of cell death and DNA fragmentation was observed in Hbo1 mutant embryos, resulting initially in the degeneration of mesenchymal tissues and ultimately in embryonic lethality. In conclusion, the primary role of HBO1 in development is that of a transcriptional activator, which is indispensable for H3K14 acetylation and for the normal expression of essential genes regulating embryonic development.