Janssens Laboratory

Epigenetic Regulation of Hematopoiesis and Leukemia

The epigenetic mechanisms that define the various cell types and tissues in our bodies involve altering the protein-DNA assembly — called chromatin — to direct changes in cellular gene expression programs. The critical protein-DNA interactions underpinning cellular differentiation often occur in small numbers of transient cell types, which poses serious technological challenges for directly studying these mechanisms in human tissues. The Janssens Lab is addressing these challenges with two main goals:

• Develop new and improved strategies to map the genome-wide occupancy of chromatin-associated proteins in single cells
• Apply these methods to characterize the epigenetic regulation of normal blood development and the epigenetic contributions to therapeutic resistance in human blood cancers

These technologies enable researchers to examine the occupancy of sparse DNA-binding transcription factors and chromatin-regulatory proteins on the DNA at a single-molecule resolution and provide a critical new lens to view the epigenetic regulation of development in heterogeneous human tissues. By coupling these methods with data integration tools powered by artificial intelligence, we are building a unified epigenetic landscape of human blood development where cellular differentiation trajectories are defined by the integration of numerous chromatin signals including markers associated with developmental gene activation and repression. This granular epigenetic roadmap of human blood development will serve as a foundation to interpret how gene-expression programs are disrupted in developmental diseases such as leukemia. Our initial efforts focus on leukemias with translocation mutations in the KMT2A/MLL1 gene. By collaborating with physician-scientists, we work to understand the epigenetic mechanisms of therapeutic resistance in human leukemia and translate these insights into novel diagnostic methods and combination therapies that improve patient outcomes.