Research

Normal gene expression is controlled, in part, through multiple regulatory systems which coordinate transcription. This includes transcription factors that recruit enzymes to express genes as well as an evolving understanding of the 3-dimensional chromatin architecture which brings together either DNA enhancer regions to activate genes or DNA insulation regions to silence genes. Structural scaffold proteins such at CTCF and the cohesin complex are essential in maintaining the integrity of local DNA structural interactions within defined neighborhoods known as topologically associating domains (TADs). These proteins provide dynamic structure within the TAD which is essential in influencing dynamic cell-type specific transcriptional programs. These chromatin regulators, including cohesin complex members, are frequently mutated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), bladder cancer, and Ewing sarcoma among many others. The functional consequences of chromatin structure in regulating lineage-specification, signal-dependent responses, and local/distant DNA structure has not been fully elucidated. Using genetically engineered mice and samples from healthy individuals and those with MDS and AML, we can delineate the requirement of suitable chromatin architecture for the function of cell-type specific transcription factors required to enforce differentiation and, in certain cases, to license pioneer function.

Active Areas of Investigation:

A. Uncover mechanisms of altered 3D chromatin in the pathophysiology of leukemia and other human cancer. We will leverage patient samples and transgenic mice to model and manipulate hematopoietic differentiation.

B. Investigate the dynamic epigenetic events that dictate hematopoietic stem cell fate determination and influence of chromatin state on transcriptional output. We will primarily use benchmarked low cell input chromatin assays on sorted cell populations.

C. Understand the non-hierarchical, non-redundant relationship between chromatin structure and transcription factor activity. Apply principles of DNA accessibility and insulation to other cellular contexts.

D. Tease out the basis for tissue specific DNA loop memory—CTCF binding sites hardwired in the genome cannot account for dynamic sub-TAD loop structure in response to stress/cytokine/differentiation.

E. Identify synthetic lethal targets and/or re-engineer chromatin loops for therapeutic purposes.