Mechanisms of chromatin assembly, gene silencing, and epigenetic inheritance
Our research aims to understand the biochemical processes that govern the establishment and maintenance preservation of silent chromatin, also referred to as heterochromatin. We use a combination of techniques, including highly purified biochemical assays, proteomic and genomic analyses, and genetic screens to study this phenomena.
Covalent modifications to DNA and histone proteins allows chromatin to act as a dynamic information hub that integrates diverse biochemical stimuli to regulate genomic DNA access for transcription. Maintaining specific gene expression is crucial for preserving cellular identity and failure to silence certain genes can lead to developmental defects or promote tumor growth.
Histone variant H3.3 and H3K9me3-containing heterochromatin:
Several histone variants found in mammalian cells play a role in various nuclear processes. We found that the histone variant H3.3 is involved in heterochromatin formation and silencing at multiple genomic regions. Heterochromatin containing H3K9me3 and H3.3 plays an important role in maintaining genome integrity by silencing transposable elements.
We found that H3K9me3, the histone variant H3.3 and its deposition factor ATRX-DAXX, and the Human Silencing Hub (HuSH) complex function together to silence retrotransposable elements in mammals.
Our study aims to identify the mechanisms and components involved in creating heterochromatin at transposons and other repetitive sequences in the genome.
Polycomb Repressive Complex 2 and H3K27me3-containing heterochromation:
The Polycomb Repressive Complex 2 (PRC2) is one component of the two main Polycomb group protein complexes that function in a collaborative crosstalk with K27 methylation on histone H3 (H3K27me3) to initiate and maintain transcriptional silencing.
Misregulation of PRC2 and H3K27me3 can cause developmental defects and specific types of cancer. We are investigating the factors that affect PRC2 recruitment and activity using both biochemical and genomic techniques.
Specific tumor types harbor clonal, monoallelic, gain-of-function mutations in genes encoding histone H3 (collectively referred to as ‘oncohistones’).
We have discovered and described a new oncoprotein known as EZHIP, which imitates the chemical process of the "H3 K27M oncohistone" in gliomas.
We aim define how these oncoproteins disrupt the functioning of chromatin machinery, including proteins like PRC2, NSD1/2, SETD2, to change chromatin structure and gene expression, thus promoting tumor growth.