Unravelling the eukaryotic post-transcriptional regulatory code

Introduction

Genomes encode instructions for cells to regulate gene activity in response to their environment. However, despite its importance for biology, medicine, and biotechnology, the underpinning regulatory code remains undeciphered.

Gene Regulation Steps

Gene regulation consists of two major steps:

1. Genes are transcribed into mRNA.
2. Post-transcriptional mechanisms regulate mRNA stability and the rate at which it is translated into proteins.

Challenges in Understanding Post-Transcriptional Regulation

The second step of gene regulation is still poorly understood because relevant parameters, such as:

• mRNA half-life
• mRNA protein binding
• Subcellular localization

are difficult to assay. The lack of understanding of post-transcriptional regulation implies that we still do not have a complete picture of the regulatory code.

Project Overview: EPIC

In EPIC, we exploit the advantages of the model eukaryote Saccharomyces cerevisiae and other species covering a broad evolutionary range to derive the first comprehensive sequence-based model of eukaryotic gene regulation.

Collaborative Approach

EPIC integrates the complementary expertise of three teams:

• Pelechano: Combines innovative high-throughput technologies to probe post-transcriptional regulation at an unprecedented scale across a broad range of species and conditions.
• Verstrepen: Utilizes synthetic biology to massively test regulatory sequences.
• Gagneur: Applies deep learning on these data to build predictive models and unravel complex regulatory instructions.

Goals and Applications

Ultimately, EPIC will enable us to decipher the actual language of gene regulation and facilitate (re)writing genomes.

EPIC will enable understanding and predicting regulation, and ultimately phenotype, from DNA, closing a major gap in basic biology. It will also open exciting avenues for applications in biotechnology and medicine, including:

• Pinpointing disease-causing mutations
• Rational design of genes, RNAs, and cells