Grijzenhout Anne, Godwin Jonathan, Koseki Haruhiko, Gdula Michal Ryszard, Szumska Dorota, McGouran Joanna F, Bhattacharya Shoumo, Kessler Benedikt M, Brockdorff Neil, Cooper Sarah
Developmental Epigenetics, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro, Tsurumi-ku, Yokohama 230-0045, Japan.
Development. 2016 Aug 1;143(15):2716-23. doi: 10.1242/dev.123935. Epub 2016 Jun 17.
The Polycomb repressive complexes PRC1 and PRC2 are key mediators of heritable gene silencing in multicellular organisms. Here, we characterise AEBP2, a known PRC2 co-factor which, in vitro, has been shown to stimulate PRC2 activity. We show that AEBP2 localises specifically to PRC2 target loci, including the inactive X chromosome. Proteomic analysis confirms that AEBP2 associates exclusively with PRC2 complexes. However, analysis of embryos homozygous for a targeted mutation of Aebp2 unexpectedly revealed a Trithorax phenotype, normally linked to antagonism of Polycomb function. Consistent with this, we observe elevated levels of PRC2-mediated histone H3K27 methylation at target loci in Aebp2 mutant embryonic stem cells (ESCs). We further demonstrate that mutant ESCs assemble atypical hybrid PRC2 subcomplexes, potentially accounting for enhancement of Polycomb activity, and suggesting that AEBP2 normally plays a role in defining the mutually exclusive composition of PRC2 subcomplexes.
多梳抑制复合物PRC1和PRC2是多细胞生物中可遗传基因沉默的关键介导因子。在此，我们对AEBP2进行了表征，AEBP2是一种已知的PRC2辅助因子，在体外已被证明可刺激PRC2活性。我们发现AEBP2特异性定位于PRC2靶位点，包括失活的X染色体。蛋白质组学分析证实AEBP2仅与PRC2复合物相关联。然而，对Aebp2靶向突变纯合子胚胎的分析意外地揭示了一种通常与多梳功能拮抗相关的三胸节表型。与此一致的是，我们在Aebp2突变胚胎干细胞（ESC）的靶位点观察到PRC2介导的组蛋白H3K27甲基化水平升高。我们进一步证明突变的ESC组装了非典型的混合PRC2亚复合物，这可能是多梳活性增强的原因，并表明AEBP2通常在定义PRC2亚复合物相互排斥的组成中发挥作用。
