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Aug 16, 2017

Seminar - A 3D CRISPR view of gene regulation (Speaker: Dr. Yarui Diao)

Dr. Yarui Diao
Ludwig Institute for Cancer Research
University of California San Diego

Date: Wed, 16-August-2017
Time: 2:00 PM
Venue: Seminar Room, L1-19, 
1/F, Laboratory Block, Faculty of Medicine Building, 
21 Sassoon Road, Pokfulam, Hong Kong

The precise transcriptional regulation in multi-cellular organisms involves the interplay of multiple components such as cis- (e.g. promoters and enhancers) and trans- (e.g. transcription factors) regulatory sequences, enabling the development of a distinct set of highly specialized cells from the same genetic blueprint. On top of genome sequence, chromatin epigenetic modifications and high-order chromatin interaction also play essential roles in transcriptional control. Through the analysis of chromatin biochemical features such as histone modification, DNA methylation, and DNase I hypersensitivity, millions of cis-regulatory elements can be predicted in the human genome. Most strikingly, these putative regulatory sequences harbor >90% of human traits and diseases associated genetic variants, leading to the theory that genetic lesions in the regulatory elements can substantially contribute to common complex human diseases. However, for most of non-coding elements, the functions and target genes in the relevant cell types remain largely unknown. In order to overcome these limits, I conducted capture Hi-C experiments with my colleagues to capture the long-range chromatin interaction centered on 19,539 gene promoters and 17,318 GWAS SNPs in 27 human cell/tissue types, providing a comprehensive map of human cis-regulome which takes 3D genome structure into consideration. Furthermore, I developed CRISPR/Cas9 based high-throughput genetic screens to study the function of non-coding elements in the native chromatin context. Using human embryonic stem cells as model system, my work leads to the identification of temporarily phenotypic enhancers and large number of enhancer-like promoters which regulate distal gene expression via long-range chromatin interaction, revealing previously unrecognized layers of gene regulation in the human genome. The combination of cutting-edge genomic and genetic technologies has provided an unprecedented opportunity for us to tackle the fundamental question of gene regulation.