An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.
An Evolutionary Conserved Epigenetic Mark of Polycomb Response Elements Implemented by Trx/MLL/COMPASS.
复制标题
DOI：
10.1016/j.molcel.2016.06.018
复制
发表时间：
2016-07-21
期刊：
影响因子：
16
通讯作者：
Shilatifard A
中科院分区：
文献类型：
--
作者：
Rickels R;Hu D;Collings CK;Woodfin AR;Piunti A;Mohan M;Herz HM;Kvon E;Shilatifard A
多梳反应元件（Polycomb Response Elements，PRE）是一种能稳定维持基因表达的特异性DNA序列。果蝇的PREs特征很好，而PREs在哺乳动物中的存在仍然存在争议。越来越多的证据支持CGIs招募多梳群复合物（PcG）的模型，然而，选择哪些CGIs子集作为PRE尚不清楚。Trx（Trithorax）在果蝇中正调控基因表达，并共同占据PRE以拮抗Polycomb依赖的沉默。在这里，我们证明，Trx依赖的H3K4二甲基化（H3K4me2）标记果蝇PRE和保持附近基因的发育表达模式。类似地，哺乳动物Trx同源物MLL1将H3K4me2沉积在可用作PRE的CpG密集区。在MLL1和H3K4me2不存在的情况下，H3K27me3水平（Polycomb Repressive Complex 2（PRC 2）的标志）在这些位点增加。通过在不存在MLL1的情况下抑制PRC2依赖性H3K27me3，我们可以拯救这些位点的表达，证明在这些位点处MLL1和PRC2活性之间的功能平衡。因此，我们的研究提供了在人类基因组中识别细胞类型特异性功能性哺乳动物PRE的规则。
Polycomb Response Elements (PREs) are specific DNA sequences that stably maintain the developmental pattern of gene expression. Drosophila PREs are well characterized, whereas the existence of PREs in mammals remains debated. Accumulating evidence supports a model in which CGIs recruit Polycomb-Group complexes (PcG), however, which subset of CGIs are selected to serve as PREs is unclear. Trithorax (Trx) positively regulates gene expression in Drosophila and co-occupies PREs to antagonize Polycomb-dependent silencing. Here, we demonstrate that Trx-dependent H3K4 dimethylation (H3K4me2) marks Drosophila PREs and maintains the developmental expression pattern of nearby genes. Similarly, the mammalian Trx homology, MLL1, deposits H3K4me2 at CpG dense regions that could serve as PREs. In the absence of MLL1 and H3K4me2, H3K27me3 levels, a mark of Polycomb Repressive Complex 2 (PRC2), increase at these loci. By inhibiting PRC2-dependent H3K27me3 in the absence of MLL1, we can rescue expression of these loci, demonstrating a functional balance between MLL1 and PRC2 activities at these sites. Thus, our study provides rules for identifying cell-type specific functional mammalian PREs within the human genome.