The dark side of the genome: systematically studying the biology of repressive elements—silencers—in the human genome: Silencer

Programme(s): H2020-EU.1.1. - EXCELLENT SCIENCE - European Research Council (ERC)

Topic(s): ERC-2020-STG - ERC STARTING GRANTS

Call for proposal: ERC-2020-STG

Funding Scheme: ERC-STG - Starting Grant

Grant agreement ID: 950655

Project description

Identification of silencers in the human genome

Most of the human genome contains regulatory elements such as promoters, enhancers and insulators that control the spatiotemporal expression of protein-coding genes. The EU-funded Silencer project will focus on the investigation of silencers, the regulatory elements that repress the transcription of genes, which have been largely understudied. Researchers will employ a novel approach to identify functional silencer elements in an unbiased way alongside their epigenetic modifications and sequence motifs. Project results will unveil new biological pathways regulated by silencers as well as the involvement of these regulatory elements in various diseases.

Objective

Less than 1.5% of the human genome contains protein coding information of the estimated 25,000 genes. The rest of the non-coding genome includes many regulatory elements that control the spatial and temporal transcription of genes. With the help of the non-coding regulatory elements, the diverse cell types and tissues of a complex human body could be derived from the combinational expression of a limited number of genes from the same copy of the genome. Most regulatory elements (REs) have been characterized extensively, e.g. promoters, enhancers and insulators. These REs have been implicated to play very important roles in cell physiology, tissue development and disease onsets. Surprisingly, one class of REs—silencers—which repress the transcription of genes, have not been systematically characterized and studied. I have developed a lentiviral system to systematically identify functional silencer elements. In the small-scale proof-of-principle experiments, by focusing on the transcriptional factor (TF) accessible DNA sequences, I showed that this system is robust to identify novel and bona fide silencers, which could be validated using complementary functional assays such as luciferase and CRISPR knockout assays. In this proposed research plan, I aim to identify silencers in an unbiased way, rather than focusing on TF accessible regions, to have a more general understanding of the biology of silencers. Based on the unbiased identification of silencers, I aim to identify a general pattern of epigenetic modifications of silencers, unique combination of sequence motifs, responsible regulatory TFs, biological pathways that are regulated by silencers, diseases that might be related to mutations in silencers, and finally better manipulation strategies of silencers.