A multidisciplinary collection of studies performed over the past decade has highlighted the critical roles for disrupted chromatin and gene regulatory mechanisms in human diseases, ranging from cancer to immune conditions and neurodevelopmental disorders. These findings have prompted the development of a wide range of new mechanistic investigations and discovery efforts toward the development of targeted therapeutics. However, the effective translation of basic mechanisms remains both slow and challenged, owing in large part to a significant gap in understanding regarding the connectivity between epigenetic factors and gene expression and cellular functions. This meeting seeks to address this gap by bringing together academic experts in chromatin and gene regulatory mechanisms with clinicians and industry experts. Collaborating and combining diverse expertise will enable us to develop more effective strategies to combat major health challenges rooted in epigenetic mechanisms. Significance This meeting will concentrate on new insights into established and emerging mechanisms of disease-related chromatin and gene regulatory proteins and protein complexes. Among the areas of emphasis will include the contrast between catalytic and non-catalytic functions of chromatin modifying factors, roles for structured and intrinsically disordered regions, the interplay between key chromatin regulatory and transcriptional complexes and other proteins that govern their stability and/or targeting and direct relationships between chromatin states and gene expression. A special focus will be given to cutting-edge and emerging technologies that further our understanding of these intricate mechanisms as well as new approaches in drug discovery and development that can accelerate translation to new medicines. Innovation Despite rapidly evolving, high-throughput genomics-centered strategies that enable intricate characterization of chromatin landscape and gene regulatory states, there remains a notable gap in understanding the mechanistic underpinnings of chromatin dysfunction and their impact on gene expression in normal and disease states. This meeting seeks to connect timely observations identified by large-scale cell fitness, gene and chromatin profiling, and proteomics efforts with biochemical, biophysical, 3D structural, and sequence-function centered work. Such a linkage is expected to maximally inform intricate mechanisms of chromatin and its associated dysfunctions in diseases, and further, to inspire new basic research and therapeutic discovery efforts in this area. By way of the topics and approaches covered, this meeting will convene a highly interdisciplinary group of basic and translationally-oriented scientists, stimulating new discussions between groups of investigators who are not routinely placed in the same meetings.