Research
1 | Elucidating the primary architecture of gene regulation
The primary architecture of chromatin is comprised of accessible regulatory elements occupied by transcription factors (TFs) and surrounding nucleosomes along linear templates of DNA. This architecture is the foundation of gene regulatory patterning during both development and disease, yet remains poorly understood. To elucidate this architecture, our lab uses a combination of approaches to map both TF occupancy patterns genome-wide as well as the primary architecture of individual chromatin fibers. For example, our group recently developed a method called Fiber-seq for stenciling the chromatin architecture of each fiber onto its underlying DNA templates using non-specific DNA N6-adenine methyltransferases (m6A-MTases). By combining m6A-MTase treated chromatin with Pacific Biosciences (PacBio) circular consensus sequencing, Fiber-seq enables nucleotide-precise chromatin accessibility, TF occupancy, and nucleosome occupancy patterns on individual multi-kilobase chromatin fibers - revealing principles guiding regulatory element activation and turnover. This straightforward approach opens a new vista on gene regulatory patterning by simultaneously profiling both epigenetic and genetic variants within a sample.
2 | Identifying regulatory DNA alterations underlying human diseases
One major factor constraining the full realization of genomics is our poor understanding of the contribution of rare non-coding genetic variation to human disease. To address this, our group leverages patient-specific epigenetic data to illuminate the functional consequences of non-coding genetic variation. Specifically, our group is interested in applying novel epigenetic technologies to primary patient samples with suspected or known rare genetic conditions to uncover non-coding regulatory DNA alterations that may be contributing to their health. We believe that simultaneously profiling both the genome and epigenome of a patient, will enable the improved clinical interpretation of rare germline or somatic genetic variants that contribute to human disease.
3 | Translating (epi)genomics into clinical medicine
Despite the significant advances in clinical genomics to date, the implementation of genomic medicine into standard clinical practice has yet to materialize for most of our patients. As the capability of genomics to improve clinical care continues to leap ahead, it is critical that we rewrite our current model for implementing genetics to match the modern practice of medicine. Our group aims to address this challenge through studying the uptake and impact of genomic testing in adult clinical practice. Specifically, we are interested in understanding the role actionable genetic findings play in clinical management, and how to overcome many of the obstacles that limit the current implementation of genomic medicine.