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Dynamic antagonism between key repressive pathways maintains the placental epigenome
Nature Cell Biology ( IF 21.3 ) Pub Date : 2023-04-06 , DOI: 10.1038/s41556-023-01114-y
Raha Weigert 1, 2 , Sara Hetzel 1 , Nina Bailly 1, 3 , Chuck Haggerty 1, 3 , Ibrahim A Ilik 4 , Philip Yuk Kwong Yung 5, 6 , Carmen Navarro 5, 6 , Adriano Bolondi 1, 3 , Abhishek Sampath Kumar 1 , Chiara Anania 7 , Björn Brändl 1, 8 , David Meierhofer 9 , Darío G Lupiáñez 7 , Franz-Josef Müller 1, 8 , Tugce Aktas 4 , Simon J Elsässer 5, 6 , Helene Kretzmer 1 , Zachary D Smith 10 , Alexander Meissner 1, 3, 11, 12
Affiliation  

DNA and Histone 3 Lysine 27 methylation typically function as repressive modifications and operate within distinct genomic compartments. In mammals, the majority of the genome is kept in a DNA methylated state, whereas the Polycomb repressive complexes regulate the unmethylated CpG-rich promoters of developmental genes. In contrast to this general framework, the extra-embryonic lineages display non-canonical, globally intermediate DNA methylation levels, including disruption of local Polycomb domains. Here, to better understand this unusual landscape’s molecular properties, we genetically and chemically perturbed major epigenetic pathways in mouse trophoblast stem cells. We find that the extra-embryonic epigenome reflects ongoing and dynamic de novo methyltransferase recruitment, which is continuously antagonized by Polycomb to maintain intermediate, locally disordered methylation. Despite its disorganized molecular appearance, our data point to a highly controlled equilibrium between counteracting repressors within extra-embryonic cells, one that can seemingly persist indefinitely without bistable features typically seen for embryonic forms of epigenetic regulation.



中文翻译:

关键抑制途径之间的动态拮抗维持胎盘表观基因组

DNA 和组蛋白 3 赖氨酸 27 甲基化通常起到抑制性修饰的作用,并在不同的基因组区室中发挥作用。在哺乳动物中,大部分基因组保持 DNA 甲基化状态,而 Polycomb 抑制复合物则调节发育基因的未甲基化富含 CpG 的启动子。与这个总体框架相反,胚胎外谱系表现出非规范的、全局中间的 DNA 甲基化水平,包括局部 Polycomb 结构域的破坏。在这里,为了更好地了解这种不寻常的景观的分子特性,我们用遗传和化学方法扰乱了小鼠滋养层干细胞的主要表观遗传途径。我们发现胚胎外表观基因组反映了持续且动态的从头甲基转移酶募集,该酶不断被 Polycomb 拮抗以维持中间的、局部无序的甲基化。尽管其分子外观杂乱无章,但我们的数据表明,胚胎外细胞内的抑制因子之间存在高度受控的平衡,这种平衡似乎可以无限期地持续存在,而无需胚胎形式表观遗传调控中常见的双稳态特征。

更新日期:2023-04-08
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