*** BME Faculty Candidate ***

Yarui Diao, Ph.D.*
Postdoctoral Fellow
Ludwig Institute for Cancer Research
San Diego

Chopping Away at "Junk" DNA: Using High-throughput CRISPR/Cas9 to Uncover the Role of Non-coding Genome Sequence

ABSTRACT

The precise transcriptional regulation involves the interplay between cis- (e.g. promoters and enhancers) and trans- (e.g. transcription factors) regulatory factors. In the human genome, millions of cis-regulatory elements have been predicted through the analysis of chromatin biochemical features. Most strikingly, these regulatory sequence harbors >90% of human diseases associated genetic variants, leading to the theory that genetic lesions in the regulatory elements can substantially contribute to human diseases. However, for most of the cis-regulatory elements, their functional consequence in the native chromatin context remains largely unknown. It is also challenging to annotate the enhancer regulatory target gene. To fill such knowledge gap, I developed high-throughput CRISPR/Cas9 screen strategies that allow for genome-wide functional characterization of non-coding regulatory sequence in the native chromatin context. My work demonstrated that many gene promoters act as long-range enhancers, and challenged the traditional concept that promoter and enhancer are distinct elements. I also mapped the promoter-centered long-range chromatin interactions in 27 human tissue types, to interpret the regulatory target gene of enhancer and disease associated genetic variants. In the future, I will integrate the cutting-edge functional genomics tools with muscle stem cell model and iPSC technology to improve the understanding of the mechanism that control muscle stem cell regenerative potency, and in the long-run, to develop stem cell based therapies to treat muscular disorders which affect aging, cancer, and a broad spectrum of human diseases.

Host: James Dahlman, Ph.D.