Global Analysis of H3K4 Methylation Defines MLL Family Member Targets and Points to a Role for MLL1-Mediated H3K4 Methylation in the Regulation of Transcriptional Initiation by RNA Polymerase II
Global Analysis of H3K4 Methylation Defines MLL Family Member Targets and Points to a Role for MLL1-Mediated H3K4 Methylation in the Regulation of Transcriptional Initiation by RNA Polymerase II
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DOI：
10.1128/mcb.00924-09
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发表时间：
2009-11-15
影响因子：
5.3
通讯作者：
Shilatifard, Ali
中科院分区：
文献类型：
--
作者：
Wang, Pengfei;Lin, Chengqi;Shilatifard, Ali
激活基因的一个共同标志是组蛋白H3(H3K4)在启动子区域的赖氨酸4上存在三甲基化。SET1/COMPASS是创始成员，也是酿酒酵母中唯一的H3K4甲基酶；然而，在哺乳动物中，至少有6个H3K4甲基酶，Set1A和Set1B以及MLL1到MLL4，存在于能够甲基化H3K4的COMPASS复合体中。为了进一步了解H3K4甲基酶的不同作用和功能靶点，我们对野生型MLL1(+/+)和MLL1(-/-)小鼠胚胎成纤维细胞(MEF)的H3K4甲基化模式进行了全基因组分析。我们发现，只有不到5%的带有这种修饰的启动子的H3K4三甲基化需要MLI1。这些基因中的许多，包括发育调节基因，如HOX基因，显示出RNA聚合酶II招募和表达水平降低，伴随着H3K4甲基化的丧失。虽然MLL1只是HOX基因子集的甲基化所必需的，但在HOX基因座的绝大多数H3K4甲基化中，MLL1和MLL2复合体的一种成分--薄荷素是必需的。然而，MLL3/MLL4和/或Set1复合体的缺失对这些MEF中HOX基因座的H3K4甲基化或其表达水平几乎没有影响。总之，这些数据为哺乳动物中COMPASS样复合体的冗余和专门化提供了洞察力，并为MLL1介导的H3K4甲基化在转录启动调控中可能发挥的作用提供了证据。
A common landmark of activated genes is the presence of trimethylation on lysine 4 of histone H3 (H3K4) at promoter regions. Set1/COMPASS was the founding member and is the only H3K4 methylase in Saccharomyces cerevisiae; however, in mammals, at least six H3K4 methylases, Set1A and Set1B and MLL1 to MLL4, are found in COMPASS-like complexes capable of methylating H3K4. To gain further insight into the different roles and functional targets for the H3K4 methylases, we have undertaken a genome-wide analysis of H3K4 methylation patterns in wild-type Mll1(+/+) and Mll1(-/-) mouse embryonic fibroblasts (MEFs). We found that Mll1 is required for the H3K4 trimethylation of less than 5% of promoters carrying this modification. Many of these genes, which include developmental regulators such as Hox genes, show decreased levels of RNA polymerase II recruitment and expression concomitant with the loss of H3K4 methylation. Although Mll1 is only required for the methylation of a subset of Hox genes, menin, a component of the Mll1 and Mll2 complexes, is required for the overwhelming majority of H3K4 methylation at Hox loci. However, the loss of MLL3/MLL4 and/or the Set1 complexes has little to no effect on the H3K4 methylation of Hox loci or their expression levels in these MEFs. Together these data provide insight into the redundancy and specialization of COMPASS-like complexes in mammals and provide evidence for a possible role for Mll1-mediated H3K4 methylation in the regulation of transcriptional initiation.