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

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.

Grant Number: 5R35GM138097-05
NIH Institute/Center: NIH
Principal Investigator: Alaji Bah