MRC Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
EMBO J. 2012 Jan 18;31(2):317-29. doi: 10.1038/emboj.2011.399. Epub 2011 Nov 4.
The role of DNA sequence in determining chromatin state is incompletely understood. We have previously demonstrated that large chromosomal segments from human cells recapitulate their native chromatin state in mouse cells, but the relative contribution of local sequences versus their genomic context remains unknown. In this study, we compare orthologous chromosomal regions for which the human locus establishes prominent sites of Polycomb complex recruitment in pluripotent stem cells, whereas the corresponding mouse locus does not. Using recombination-mediated cassette exchange at the mouse locus, we establish the primacy of local sequences in the encoding of chromatin state. We show that the signal for chromatin bivalency is redundantly encoded across a bivalent domain and that this reflects competition between Polycomb complex recruitment and transcriptional activation. Furthermore, our results suggest that a high density of unmethylated CpG dinucleotides is sufficient for vertebrate Polycomb recruitment. This model is supported by analysis of DNA methyltransferase-deficient embryonic stem cells.
DNA 序列在决定染色质状态中的作用尚不完全清楚。我们之前已经证明，来自人类细胞的大染色体片段可以在小鼠细胞中重现其天然的染色质状态，但局部序列的相对贡献及其基因组背景仍然未知。在这项研究中，我们比较了同源的染色体区域，其中人类基因座在多能干细胞中建立了明显的 Polycomb 复合物募集位点，而相应的小鼠基因座则没有。我们使用在小鼠基因座上进行的重组介导的盒交换，确定了局部序列在编码染色质状态中的首要地位。我们表明，染色质二价性的信号在一个二价域中是冗余编码的，这反映了 Polycomb 复合物募集和转录激活之间的竞争。此外，我们的结果表明，高密度未甲基化的 CpG 二核苷酸对于脊椎动物 Polycomb 的募集是足够的。这一模型得到了缺乏 DNA 甲基转移酶的胚胎干细胞分析的支持。
