Functional characterization and therapeutic targeting of gene regulatory elements

講演要旨

Nucleotide variation in gene regulatory elements is a major determinant of phenotypes including morphological diversity between species, human variation and human disease. Despite continual progress in the cataloging of these elements, little is known about the code and grammatical rules that govern their function. Deciphering the code and their grammatical rules will enable high-resolution mapping of regulatory elements, accurate interpretation of nucleotide variation within them and the design of sequences that can deliver molecules for therapeutic purposes. To this end, we are using massively parallel reporter assays (MPRAs) to simultaneously test the activity of thousands of gene regulatory elements and variants in parallel. Regulatory elements can also serve as therapeutic targets. By targeting regulatory elements via CRISPR activation (CRISPRa), we show that they can be used to rescue a variety of haploinsufficient diseases (having ~50% dosage reduction due to having only one functional allele). In addition, utilizing CRISPRa to engineer adipocytes and adipose organoids to outcompete tumors for nutrients, we show that they can be used as a novel cancer therapy, termed Adipose Manipulation Transplantation (AMT).