BE Seminar: “Robust CRISPR/Cas-based epigenome editing technologies for precision human cell engineering and mechanistic dissection of pathological gene expression” (Isaac Hilton, Rice University)
October 19 at 3:30 PM - 4:30 PM
Recent advances in CRISPR/Cas-based epigenome editing technologies have enabled programmable control over human gene expression, chromatin states, and genomic organization. Consequently, these emerging technologies have created new opportunities to engineer human cells for therapeutic benefit and catalyzed innovative ways to functionally interrogate gene regulatory mechanisms in situ. Toward these ends, we have recently developed new capabilities in the context of CRISPR/Cas-based transcriptional activation (CRISPRa) modalities. First, we have identified and repurposed key segments from natural human transcription factors to build potent and compact multipartite transactivation modules and in turn build the CRISPR-DREAM platform. CRISPR-DREAM is specific, robust across mammalian cell types, efficacious at diverse human regulatory elements, and well tolerated in therapeutically important primary cells – including T cells, MSCs, neurons, and iPSCs. We have also leveraged the small size and potency of CRISPR-DREAM components to generate all-in-one CRISPRa AAV systems that expand opportunities for in vivo gene control. Second, in unpublished studies, we have isolated intrinsically disordered regions (IDRs) from oncogenic fusion proteins associated with therapeutically intractable hematologic malignancies and nuclear phase separation. We find that different IDR compositions exhibit distinct propensities for nuclear import and biomolecular condensation in human cell nuclei. We demonstrate using precision CRISPR-based targeting of IDRs to human loci, that levels of phase separation can be directly proportional to target gene activation. Interestingly we also find that while core transcriptomic network changes are shared among certain oncogenic IDR fusion proteins, phase separation behaviors and genomic engagement occur in discrete ways – suggesting divergent IDR-driven routes to cellular oncogenesis, the control over which could create new possibilities for tailored therapeutic approaches.
Isaac Hilton, Ph.D.
Assistant Professor, CPRIT Scholar in Cancer Research, Department of Bioengineering, Department of BioSciences, BioScience Research Collaborative, Rice University
Isaac Hilton is an Assistant Professor of Bioengineering at Rice University and a CPRIT scholar in cancer research. The goal of the work in the Hilton lab is to better understand how human cells function and apply these insights for better genetic medicines and cell-based therapeutics. To accomplish this overarching goal, the Hilton lab develops biotechnologies to elucidate and reshape how human genes are expressed, how human cells run biological programs, and how disease phenotypes manifest and respond to defined perturbations. Dr. Hilton earned his PhD in Genetics and Molecular Biology at the University of North Carolina at Chapel Hill, where he was awarded two NIH pre-doctoral training grants in both Genetics and Virology, to study human gene regulation, genomics, and tumor virology within the Lineberger Comprehensive Cancer Center and Department of Microbiology and Immunology. He then completed his postdoctoral training in the Department of Biomedical Engineering and the Center for Genomic and Computational Biology at Duke University. At Duke, Dr. Hilton and his colleagues developed the first programmable CRISPR/Cas9-based acetyltransferase, for which Dr. Hilton earned the Center for Biomolecular and Tissue Engineering Postdoctoral Achievement Award. In 2018, Dr. Hilton was awarded a first-time faculty recruitment award from the Cancer Prevention and Research Institute of Texas (CPRIT) to initiate the research efforts in his lab in the Department of Bioengineering at Rice University in Houston, Texas. Since this time the Hilton lab’s mission has been generously enabled by other funding agencies, including the Dunn Foundation, DARPA, the NIH NIBIB, NIGMS, and NHGRI. The Hilton lab is also interested in translating and commercializing their work, which has led to several patents related to genome and epigenome editing and human cell engineering. Finally, Dr. Hilton and his entire team are committed to fostering a supportive and inclusive environment in which to train a diverse and societally representative cadre of future leaders in biomedical research and bioengineering.