Institute of Molecular Biology, National Chung Hsing University, Taichung 40227, Taiwan.
Department of Minimally Invasive Skull Base Neurosurgery, Neurological Institute, Taichung Veterans General Hospital, Taichung 40705, Taiwan; Department of Physical Therapy, Hung Kuang University, Taichung 43302, Taiwan.
Biochim Biophys Acta Mol Cell Res. 2021 Oct;1868(11):119100. doi: 10.1016/j.bbamcr.2021.119100. Epub 2021 Jul 16.
Heterochromatin, a type of condensed DNA in eukaryotic cells, has two main categories: Constitutive heterochromatin, which contains H3K9 methylation, and facultative heterochromatin, which contains H3K27 methylation. Methylated H3K9 and H3K27 serve as docking sites for chromodomain-containing proteins that compact chromatin. M33 (also known as CBX2) is a chromodomain-containing protein that binds H3K27me3 and compacts chromatin in vitro. However, whether M33 mediates chromatin compaction in cellulo remains unknown. Here we show that M33 compacts chromatin into DAPI-intense heterochromatin domains in cells. The formation of these heterochromatin domains requires H3K27me3, which recruits M33 to form nuclear bodies. G9a and SUV39H1 are sequentially recruited into M33 nuclear bodies to create H3K9 methylated chromatin in a process that is independent of HP1α. Finally, M33 decreases progerin-induced nuclear envelope disruption caused by loss of heterochromatin. Our findings demonstrate that M33 mediates the formation of condensed chromatin by forming nuclear bodies containing both H3K27me3 and H3K9me3. Our model of M33-dependent chromatin condensation suggests H3K27 methylation corroborates with H3K9 methylation during the formation of facultative heterochromatin and provides the theoretical basis for developing novel therapies to treat heterochromatin-related diseases.
异染色质是真核细胞中一种浓缩的 DNA 类型，有两种主要类别：组成型异染色质，其含有 H3K9 甲基化；和兼性异染色质，其含有 H3K27 甲基化。甲基化的 H3K9 和 H3K27 作为含有 chromodomain 的蛋白质的停靠位点，这些蛋白质使染色质紧缩。M33（也称为 CBX2）是一种含有 chromodomain 的蛋白质，它结合 H3K27me3，并在体外使染色质紧缩。然而，M33 是否在细胞内介导染色质紧缩尚不清楚。在这里，我们显示 M33 将染色质紧缩成细胞内 DAPI 强烈的异染色质域。这些异染色质域的形成需要 H3K27me3，它招募 M33 形成核体。G9a 和 SUV39H1 顺序被招募到 M33 核体中，在一个不依赖于 HP1α 的过程中创建 H3K9 甲基化染色质。最后，M33 减少了由异染色质丢失引起的早衰素诱导的核膜破裂。我们的发现表明，M33 通过形成含有 H3K27me3 和 H3K9me3 的核体来介导浓缩染色质的形成。我们的 M33 依赖性染色质紧缩模型表明，在形成兼性异染色质的过程中，H3K27 甲基化与 H3K9 甲基化协同作用，并为开发治疗异染色质相关疾病的新疗法提供了理论基础。
