Mechanisms of chromatin assembly, gene silencing, and epigenetic inheritance
Our research explores the intricate biochemical and molecular processes that govern the formation, maintenance, and inheritance of silent chromatin—also known as heterochromatin. By integrating biochemical assays, proteomic and genomic analyses, and unbiased genetic screens, we aim to decode the fundamental mechanisms that shape chromatin dynamics.
Covalent modifications of DNA and histone proteins transform chromatin into a versatile regulatory platform, fine-tuning DNA accessibility for transcription. This dynamic regulation is essential for preserving cellular identity, and disruptions in gene silencing can lead to developmental disorders or fuel oncogenesis.
H3.3 and H3K9me3: Guardians of Genome Integrity
Histone variants like H3.3 have critical roles in orchestrating nuclear processes. Our work has revealed that heterochromatin enriched with the histone variant H3.3 and the H3K9me3 modification is critical for silencing genes and maintaining genome stability by repressing retrotransposable elements.
We study key players—including H3K9me3, H3.3, the ATRX-DAXX deposition complex, and the Human Silencing Hub (HuSH) complex—that safeguard mammalian genomes from retrotransposon activity. Recently, we identified HuSH2, a second complex centered around TASOR2, a paralog of the TASOR protein in HuSH. While HuSH represses LINE-1 retrotransposons, HuSH2 targets KRAB-ZNFs and interferon response genes, highlighting distinct regulatory roles for these complexes in chromatin silencing.
Building on these findings, our ongoing studies aim to define the molecular mechanisms and identify the key components that establish heterochromatin at transposable elements and other repetitive sequences. This work seeks to elucidate fundamental principles of epigenetic regulation and genome stability, with implications for understanding how chromatin dynamics contribute to cellular homeostasis and disease.
Polycomb Repressive Complex 2: Silencing Genes, Shaping Fates
The Polycomb Repressive Complex 2 (PRC2) is a master regulator of transcriptional silencing, wielding its influence through H3K27me3, a histone modification that directs gene repression during development and cellular differentiation.
When PRC2 or H3K27me3 becomes dysregulated, the consequences can be dire—manifesting as developmental disorders or fueling cancer. Our research delves deep into the molecular mechanisms that control PRC2 activity, leveraging biochemical and genomic tools to reveal how this complex exerts its influence.
Certain cancers exploit PRC2 dysfunction through "oncohistones," mutated histone H3 variants like H3K27M, which derail normal epigenetic regulation in gliomas. We identified EZHIP, a novel oncoprotein that mimics the disruptive effects of oncohistones by competitively inhibiting PRC2. Together, these molecules reprogram chromatin structure, reshaping gene expression to drive tumorigenesis.
Our work aims to uncover the precise mechanisms through which oncohistones, EZHIP, and other chromatin regulators such as NSD1/2 and SETD2 alter chromatin landscapes. By decoding how these aberrations promote cancer, we aim to identify new therapeutic targets, paving the way for innovative interventions in cancer biology.