Systematic elucidation of genetic mechanisms underlying cholesterol uptake
The overall goal of the Sherwood lab is to advance genomic and precision medicine applications through high-throughput, multi-disciplinary science. In this talk, I will review a suite of high-throughput genomic and cellular perturbation platforms using CRISPR-based genome editing that the lab has developed to improve our understanding of genetic disease, gene regulation, and genome editing outcomes.
This talk will focus on recent efforts using combined analysis of rare coding variants from the UK Biobank and genome-scale CRISPR-Cas9 knockout and activation screening to improve the identification of genes, coding variants, and non-coding variants whose alteration impacts serum LDL cholesterol (LDL-C) levels. Through these efforts, we show that dysfunction of the RAB10 vesicle transport pathway leads to hypercholesterolemia in humans and mice by impairing surface LDL receptor levels. Further, we demonstrate that loss of function of OTX2 leads to robust reduction in serum LDL-C levels in mice and humans by increasing cellular LDL-C uptake. Finally, we unveil an activity-normalized base editing screening framework to better understand the impacts of coding and non-coding variation on serum LDL-C levels, altogether providing a roadmap for further efforts to dissect complex human disease genetics.
Date: 21 October 2022, 14:00 (Friday, 2nd week, Michaelmas 2022)
Venue: Mathematical Institute, Woodstock Road OX2 6GG
Venue Details: L3
Speaker: Prof Richard Sherwood (Harvard Medical School)
Organising department: Mathematical Institute
Organiser: Sara Jolliffe (University of Oxford)
Organiser contact email address: sara.jolliffe@maths.ox.ac.uk
Host: Dr Peter Minary (University of Oxford)
Part of: Mathematical Biology and Ecology
Booking required?: Not required
Audience: Members of the University only
Editor: Sara Jolliffe