MHI Seminar Series presents MHI Keynote Speaker: Rajan Jain, M.D., William Wikoff Smith Associate Professor, Dept of Medicine and Cell & Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA

Summary of Seminar:  The Jain Laboratory’s work broadly falls into two major themes. First, they are defining the molecular factors regulating 3D chromatin spatial positioning. Their work was the first to show that lamina-chromatin interactions are required for lineage restriction and cellular differentiation in mammals. They demonstrated that pathogenic LMNA variants impact cell type-specific lamina-chromatin interactions in regions with specific molecular and epigenetic features and enriched for non-cardiac genes. This loss of peripheral chromatin organization results in upregulation of non-cardiac fate genes in mutant cardiac tissues. They have also generated an atlas of lamina-chromatin interactions across multiple human cell types and defined a new, intermediate peripheral heterochromatin state. Most recently, their data demonstrate that mechanical inputs are critical to LAD organization to maintain cell identity. Collectively, their work has shown that spatial positioning safeguards cellular identity and contributes to human disease. This work has been supported by Dr. Jain’s NIH New Innovator and R35 awards (DP2HL147123, R35HL166663) and expanded by their interactions with the 4D Nucleome Consortium. A second major research theme is deciphering the role of genome folding in development and cell state transitions, motivated by their interest in BET (Bromodomain Extraterminal Domain) Proteins. They revealed that BRD4 directs genome folding independent of its transcriptional activity, and this folding is essential for normal cardiac neural crest differentiation. This work demonstrated the functional relevance of genome folding to organogenesis.