Mechanisms that establish, maintain, and disrupt repressive chromatin
Our laboratory investigates how cells establish and maintain repressive chromatin states. We seek to determine how nucleosome composition, histone modifications, and chromatin-regulatory proteins are coordinated to control genome accessibility and gene expression.
We combine biochemistry, structural biology, quantitative proteomics, functional genomics, and genetic approaches to connect molecular mechanism with chromatin behavior in cells. Our studies address how repressive domains form at defined genomic regions, how they are restored after chromatin disruption, and how their failure alters genome stability, cellular identity, and disease.
Heterochromatin assembly, transposon silencing, and genome stability
A major area of our research concerns how repetitive DNA and transposable elements are packaged into heterochromatin. We investigate how nucleosome assembly and histone modification are coordinated to produce chromatin states that resist transcription and limit the mobilization of repetitive sequences. We are particularly interested in how distinct molecular activities reinforce one another and whether the mechanisms that assemble specialized chromatin can be separated from those that directly repress transcription.
These studies seek to define general principles of epigenetic memory and chromatin resilience. They also provide a mechanistic framework for understanding how defects in heterochromatin maintenance lead to transposable-element activation, altered immune signaling, loss of cellular identity, and genome instability.
Polycomb-mediated gene regulation in development and cancer
A second major area of our research focuses on how Polycomb-repressed chromatin is established, propagated, and spatially constrained at developmental genes. We investigate how chromatin context, pre-existing histone modifications, nucleic acids, regulatory co-factors, and post-translational modifications of non-histone proteins control the biochemical activity and conformational state of Polycomb complexes. Our goal is to determine how these regulatory inputs govern the initiation and spread of repressive histone methylation while preventing inappropriate gene silencing elsewhere in the genome.
We are particularly interested in how biochemical feedback at individual nucleosomes produces stable but spatially restricted chromatin domains. These studies examine how chromatin-modifying activities respond to the composition and modification state of their substrates, how opposing chromatin pathways establish domain boundaries, and how repressive chromatin is remodeled as cells differentiate or change state.
We also investigate how mutations in histones and chromatin regulators reprogram these control mechanisms in pediatric brain tumors and other cancers. Rather than simply increasing or decreasing repression, these alterations can redistribute histone modifications, change chromatin domain boundaries, and stabilize abnormal transcriptional programs. By linking biochemical mechanism to genome-wide chromatin organization and cellular phenotype, we seek to identify the molecular dependencies that arise when epigenetic regulation is rewired in disease.