Genomics, Biotechnology Center, Center for Molecular and Cellular Bioengineering, University of Technology Dresden, 01307 Dresden, Germany.
European Molecular Biology Laboratory Australia Node for Single Molecule Science, ARC Centre of Excellence in Advanced Molecular Imaging, School of Medical Sciences, University of New South Wales, Sydney 2052, Australia.
Genes Dev. 2019 May 1;33(9-10):550-564. doi: 10.1101/gad.322222.118. Epub 2019 Mar 6.
Epigenetic modifications can maintain or alter the inherent symmetry of the nucleosome. However, the mechanisms that deposit and/or propagate symmetry or asymmetry are not understood. Here we report that yeast Set1C/COMPASS (complex of proteins associated with Set1) is dimeric and, consequently, symmetrically trimethylates histone 3 Lys4 (H3K4me3) on promoter nucleosomes. Mutation of the dimer interface to make Set1C monomeric abolished H3K4me3 on most promoters. The most active promoters, particularly those involved in the oxidative phase of the yeast metabolic cycle, displayed H3K4me2, which is normally excluded from active promoters, and a subset of these also displayed H3K4me3. In wild-type yeast, deletion of the sole H3K4 demethylase, Jhd2, has no effect. However, in monomeric Set1C yeast, Jhd2 deletion increased H3K4me3 levels on the H3K4me2 promoters. Notably, the association of Set1C with the elongating polymerase was not perturbed by monomerization. These results imply that symmetrical H3K4 methylation is an embedded consequence of Set1C dimerism and that Jhd2 demethylates asymmetric H3K4me3. Consequently, rather than methylation and demethylation acting in opposition as logic would suggest, a dimeric methyltransferase and monomeric demethylase cooperate to eliminate asymmetry and focus symmetrical H3K4me3 onto selected nucleosomes. This presents a new paradigm for the establishment of epigenetic detail.
表观遗传修饰可以维持或改变核小体的固有对称性。然而，沉积和/或传播对称性或非对称性的机制尚不清楚。在这里，我们报告酵母 Set1C/COMPASS（与 Set1 相关的蛋白质复合物）是二聚体，因此对称地上调组蛋白 3 Lys4（H3K4me3）在启动子核小体上。将二聚体界面突变为单体使 Set1C 使大多数启动子上的 H3K4me3 失活。最活跃的启动子，特别是那些参与酵母代谢周期氧化阶段的启动子，显示出通常排除在活性启动子之外的 H3K4me2，并且其中一部分还显示出 H3K4me3。在野生型酵母中，唯一的 H3K4 去甲基酶 Jhd2 的缺失没有影响。然而，在单体 Set1C 酵母中，Jhd2 的缺失增加了 H3K4me2 启动子上的 H3K4me3 水平。值得注意的是，Set1C 与延伸聚合酶的结合不受单体化的影响。这些结果表明，对称的 H3K4 甲基化是 Set1C 二聚体的嵌入式后果，并且 Jhd2 去甲基化不对称的 H3K4me3。因此，不是像逻辑所暗示的那样，甲基化和去甲基化作用相反，而是二聚体甲基转移酶和单体去甲基酶合作消除不对称性，并将对称的 H3K4me3 集中在选定的核小体上。这为建立表观遗传细节提出了一个新的范例。
