A histone H3 lysine 27 demethylase regulates animal posterior development
A histone H3 lysine 27 demethylase regulates animal posterior development
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DOI：
10.1038/nature06192
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发表时间：
2007-10-11
期刊：
影响因子：
64.8
通讯作者：
Shi, Yang
中科院分区：
文献类型：
--
作者：
Lan, Fei;Bayliss, Peter E.;Shi, Yang
最近发现的大量组蛋白去甲基化酶表明，这些酶在调节组蛋白甲基化动力学中起着核心作用。组蛋白H3K27三甲基化（H3K27me3）与polycomb-群蛋白介导的Hox基因抑制和动物体模式、x染色体失活以及可能维持胚胎干细胞（ESC）身份有关。由于甲基化酶EZH2的过度表达而导致的H3K27甲基化失衡与转移性前列腺癌和侵袭性乳腺癌有关。我们发现含有jmjdc结构域的相关蛋白UTX和JMJD3可以催化H3K27me3/2的去甲基化。UTX在原代人成纤维细胞中许多HOX基因的转录起始位点周围富集，在这些位点上HOX基因是差异表达的，但在ESCs中被选择性地排除在HOX位点之外，在ESCs中HOX基因基本上是沉默的。同样，RNA干扰抑制UTX导致一些HOX基因启动子的H3K27me3水平升高。重要的是，斑马鱼UTX同源物的morpholino寡核苷酸抑制导致hox基因的错误调控和显著的后部发育缺陷，这部分是由野生型而非催化活性的人类UTX所拯救的。综上所述，这些发现确定了一个小的H3K27去甲基化酶家族，在H3K27甲基化调节和动物前后发育中具有重要的进化保守作用。
The recent discovery of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. Histone H3K27 trimethylation (H3K27me3) has been linked to polycomb-group-protein-mediated suppression of Hox genes and animal body patterning, X-chromosome inactivation and possibly maintenance of embryonic stem cell (ESC) identity. An imbalance of H3K27 methylation owing to overexpression of the methylase EZH2 has been implicated in metastatic prostate and aggressive breast cancers. Here we show that the JmjC-domain-containing related proteins UTX and JMJD3 catalyse demethylation of H3K27me3/2. UTX is enriched around the transcription start sites of many HOX genes in primary human fibroblasts, in which HOX genes are differentially expressed, but is selectively excluded from the HOX loci in ESCs, in which HOX genes are largely silent. Consistently, RNA interference inhibition of UTX led to increased H3K27me3 levels at some HOX gene promoters. Importantly, morpholino oligonucleotide inhibition of a zebrafish UTX homologue resulted in mis-regulation of hox genes and a striking posterior developmental defect, which was partially rescued by wild-type, but not by catalytically inactive, human UTX. Taken together, these findings identify a small family of H3K27 demethylases with important, evolutionarily conserved roles in H3K27 methylation regulation and in animal anterior-posterior development.