UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development
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DOI：
10.1038/nature06145
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发表时间：
2007-10-11
期刊：
影响因子：
64.8
通讯作者：
Helin, Kristian
中科院分区：
文献类型：
--
作者：
Agger, Karl;Cloos, Paul A. C.;Helin, Kristian
三胸和多梳蛋白是染色质修饰物，在细胞命运的发育、分化和维持的表观遗传调控中发挥关键作用(1-3)。多梳抑制复合体2(PRC2)通过催化组蛋白H3(H3K27me2/ME3)上Lys 27的二甲基化和三甲基化来介导转录抑制(3)。由于PRC2复合体在抑制大量参与躯体过程的基因方面具有重要作用，H3K27me3标记与干细胞独特的表观遗传状态有关(4-7)。在胚胎发育和干细胞分化的特定阶段，H3K27me3标记的迅速下降表明可能存在H3K27me3特异的组蛋白去甲基酶。在这里，我们显示了含有人类JmjC结构域的蛋白UTX和JMJD3使组蛋白H3上的Lys 27三甲基化。此外，我们还证明了JMJD3的异位表达导致H3K27me3水平的显著下降，并导致体内多梳蛋白的去定位。与HOX基因相关的H3K27me3水平在分化过程中的强烈下降一致，我们表明UTX直接与HOXB1基因结合，是其激活所必需的。最后，秀丽线虫JMJD3同源基因F18E9.5的突变或表达抑制，会导致性腺发育异常。综上所述，这些结果表明，UTX/JMJD3蛋白调控的H3K27me3去甲基化是正常发育所必需的。此外，最近的证据表明，UTX与H3K4me3组蛋白甲基转移酶Mll2(参考文献2)有关。8)支持一种模型，在该模型中，抑制标记的协调移除、多梳基团的移位和激活标记的沉积对于细胞分化过程中转录的严格调控是重要的。
The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates(1-3). The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3)(3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells(4-7). The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.