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

Project Information

Silencer

Grant agreement ID: 950655

DOI

10.3030/950655

EC signature date 4 November 2020

Start date 1 February 2021

End date 31 January 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 750 000,00

EU contribution

€ 1 750 000,00

Coordinated by

ACADEMISCH ZIEKENHUIS LEIDEN
Netherlands

Periodic Reporting for period 3 - Silencer (The dark side of the genome: systematically studying the biology of repressive elements—silencers—in the human genome)

Reporting period: 2024-02-01 to 2025-07-31

Summary of the context and overall objectives of the project

There are 3 billion base pairs in our human genome. Surprisingly, only 2% of such vast information codes for approximately 20,000 genes, which encode for proteins—the basic building blocks of cells1. The remaining 98% of the human genome, sometimes referred to as the dark side of the human genome, contains many non-coding regulatory elements (NCREs), which control the combinational expression of the limited number of genes to form diverse cell types and tissues of a complex human body, all from the same copy of the genome. Although we have learned a lot about the biology of many different NCREs, our knowledge of silencers—one of the important categories of NCRE—is surprisingly limited. Furthermore, over the past decades, the pharmaceutical values of targeting genes/proteins to treat diseases have been extensively exploited, leading to many successful drugs. However, the therapeutic potential of 98% of the non-coding human genome, especially the silencers, has not been unlocked. Such limitation is not only because of the large size of the non-coding genome, but also the lack of functional understanding of NCREs in different tissues and contexts. In the project Silencer, I aim to identify silencers in the human genome in an unbiased fashion. I expect that there are many silencers present in the human genome with unique signatures. And these silencers will play important roles in normal physiology, tissue development and disease onset.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

So far, we have generated the unbiased silencer screening libraries that aim to identify silencers from one individual chromosome. We have performed silencer screenings to identify potential silencers related to haploinsufficiency and SNP containing sequences that have been shown to associate with human diseases. We are busy validating the potential hits and studying the biology related to them. We also established cell lines for determining the TFs around silencers. A proof-of-concept single-cell experiment has been performed to study the silencer-regulated cells successfully.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

We expect to identify and define important functions of silencers in both fundamental biology and human diseases.

Silencer elements and their proposed mechanisms in gene regulation.