Molecular Mechanisms of Chromatin Remodeling and Deacetylation

About This Grant

Project Summary Chromatin structure and function are dynamically regulated by ATP-dependent chromatin remodelers and Sirtuin histone deacetylases, two critical enzyme families that play pivotal roles in DNA transcription, replication, repair, and genome stability. Chromatin remodelers use ATP hydrolysis to reposition and modify nucleosomes, while Sirtuins, NAD⁺-dependent histone deacetylases, modulate chromatin states through site-specific histone deacetylation. These enzymes often work in concert to fine-tune chromatin accessibility and gene expression. Although their roles have been studied to some extent, their precise mechanisms and the nature of their interplay remain poorly defined, underscoring the need for further investigation into their complex interactions with chromatin. Building on my laboratory’s strong track record in chromatin biology, structural studies, and functional assays, as well as compelling preliminary data, my research program aims to uncover the individual molecular mechanisms of chromatin remodelers and Sirtuins, as well as focus on their coordination in regulating nucleosome dynamics and chromatin structure. Supported by a highly collaborative network and innovative methodologies, this work aims to tackle fundamental unanswered questions in chromatin biology, with the potential to drive significant advancements in the field Two major themes drive this research. The first explores ATP-dependent chromatin remodelers, specifically CHD and ISWI ATPases, examining their catalytic mechanisms, substrate specificity, and the influence that histone post-translational modifications (PTMs) have on their remodeling activity. State-of-the-art approaches, including high-resolution cryo-electron microscopy (cryo-EM), molecular dynamics simulations, and advanced biochemical assays, will reveal the dynamics of remodeling cycles and interactions with chromatin. The second theme focuses on the Sirtuin family of deacetylases and their interplay with chromatin remodelers. Structural and functional studies, coupled with tools like synthetic nucleosomes with defined PTMs, real-time FRET-based translocation assays, and cross-linking mass spectrometry, will provide unprecedented insights into their coordination and regulatory roles. By leveraging our expertise, robust preliminary data, and a world-class support network, this research will not only advance our understanding of chromatin modulation but will also drive the entire field forward, offering critical insights into gene regulation, genome integrity, and the development of therapeutic strategies targeting chromatin dysfunction in diseases such as cancer and neurodegeneration.