Role of DNA Methylation in Liquid-liquid Phase Separation-mediated Heterochromatin Formation

项目总结/摘要 染色质的结构和动力学控制着DNA对调控因子的可及性， 转录、复制、重组和DNA损伤修复。染色质相关蛋白的PTM， DNA甲基化是一种复杂的表观遗传学机制，调控基因表达和染色质 organization.这些机制之间的相互作用产生协同或拮抗的相互作用， （i）常染色质：轻包装的染色质，富含基因，通常处于活性状态 转录或（ii）异染色质：紧密包装和浓缩的染色质，主要含有沉默的基因。 这种分区的分子机制尚未完全了解。最近的研究表明， 异染色质可以通过多价相互作用驱动液-液相分离（LLPS）进行组装 修饰的组蛋白尾部和结合这些表观遗传修饰的蛋白质之间的联系。然而，在这方面， 异染色质还高度富集甲基化DNA，其是可调节的，并由 周围的组蛋白修饰结合蛋白和酶。甲基化DNA结合蛋白和 DNA甲基化的模式与LLPS介导的组蛋白修饰机制协调， 异染色质的组装尚未完全了解。本提案将填补这些知识空白。

Project Summary/Abstract The structure and dynamics of chromatin control the accessibility of DNA to regulatory factors during transcription, replication, recombination and DNA damage repair. PTMs of chromatin-associated proteins and DNA methylation are complex epigenetic mechanisms that regulate gene expression and chromatin organization. The interplay between these mechanisms generate synergistic or antagonistic interactions that partition chromatin into (i) euchromatin: lightly packed chromatin, enriched in genes often under active transcription or (ii) heterochromatin: tightly packed and condensed chromatin, containing mostly silenced genes. The molecular mechanisms underlying this partition is not fully understood. Recent studies demonstrate that heterochromatin can assemble through liquid-liquid phase separation (LLPS) driven by multivalent interactions between modified histone tails and the proteins that bind these epigenetic modifications. However, heterochromatin is also highly enriched in methylated DNA, which is reciprocally regulating, and regulated by the surrounding histone modification binding proteins and enzymes. How methylated DNA binding proteins and the patterns of DNA methylation co-ordinate with the histone modification machinery in the LLPS-mediated assembly of heterochromatin is not fully understood. This proposal will address these gaps in knowledge.