A new paradigm for SWI/SNF chromatin function; the ATPase dependent remodeler is a component of the MeCP2 complex

DNA甲基化是许多基因表观遗传沉默的主要决定因素。靶向DNA甲基化及其结果，即转录沉默的机制与人类发育和疾病有关。在人类疾病中，DNA甲基化和组蛋白去乙酰化控制的重要变化的例子包括智力低下(脆性X综合征，Rett综合征)和致癌。有证据表明，甲基化特异性蛋白家族(甲基-CpG结合域，MBD)具有与甲基化序列结合并抑制转录的能力。然而，针对CpG甲基化的机制仍然不清楚。此外，越来越明显的是，甲基-CpG结合蛋白并不是唯一沉默转录的蛋白，其他表观遗传成分被认为影响转录(即SWI-SNF激活复合体)。这项拨款提案集中于我们最新的工作，展示了一种新的转录抑制的分子机制，扩展了MeCP2介导的机制。我们的结果首次表明人SWI-SNF ATPase复合体是一个转录抑制物，并被鉴定为MeCP2-组蛋白去乙酰化酶抑制物复合体的一部分。这些数据扩展了DNA甲基化、染色质重塑和转录调控之间的机制联系。更重要的是，实验结果可能导致重新审视MeCP2转录抑制和表观遗传修饰背后的机制基础。我们的发现为SWI-SNF作为MeCP2甲基化依赖的沉默复合体的一个组成部分提供了一种新的范式。

DNA methylation is a major determinant in the epigenetic silencing of many genes. The mechanisms underlying that targeting of DNA methylation and the consequence, that is, transcriptional silencing are relevant to human development and disease. Examples of the significance of alterations in the controls of DNA methylation and histone deacetylation in human disease include mental retardation (fragile X syndrome, Rett syndrome) and carcinogenesis. Evidence is emerging that a family of methylation specific (methyl-CpG binding domain, MBD) proteins have the capacity to bind to methylated sequences and repress transcription. The mechanisms that target CpG methylation however still remain unclear. Furthermore, it is becoming increasingly evident that methyl-CpG binding proteins are not alone in silencing transcription and other epigenetic components are thought to influence transcription (namely, SWI-SNF activation complex). This grant proposal concentrates on our most recent work which demonstrates a new molecular mechanism of transcriptional repression extending the mechanism mediated by MeCP2. Our results are the first to show that the human SWI-SNF ATPase complex is a transcriptional repressor and is identified as part of the MeCP2-histone deacetylase repressor complex. This data extends the mechanistic link between DNA methylation, chromatin remodelling and transcriptional regulation. More importantly, the experimental findings could lead to a re-examination of the mechanistic basis behind MeCP2 transcriptional repression and epigenetic modification. Our findings suggest a new paradigm for SWI-SNF as a component of the MeCP2 methylation dependent silencing complex.