ERC Starting Grant for Daniel Ibrahim

Synthetic DNA to reveal genetic switches

We already know in great detail how proteins are encoded in the DNA sequence of our genes. However, our understanding how one gene is active in one cell, but inactive in another is much more limited. While it's clear that the information for this gene activity is also “programmed” in DNA, we have yet to crack the regulatory code. Daniel Ibrahim, a junior research group leader at the Berlin Institute of Health at Charité (BIH) and a scientist at the Max Planck Institute for Molecular Genetics (MPIMG), is dedicated to unraveling this mystery. He synthesizes long pieces of DNA consisting of tens of thousands of base pairs in the lab, introduces them into cells, and assesses their impact on gene activity. To help achieve his groundbreaking work, he has been awarded a Starting Grant of 1.5 million euros over five years by the European Research Council (ERC).

Daniel Ibrahim is an expert in the field of gene expression, which involves studying the regulation of gene activity. “During embryonic development, the timing, location, and frequency of gene expression – that is, how genes are transcribed and translated to protein – are precisely controlled,” explains the molecular biologist. “This process is critical throughout life, especially during the differentiation of stem cells into specific cell types like blood or skin cells. Any errors during this process can result in severe diseases.”

Focus on regulatory regions in the genome

Errors affecting gene expression are typically found in the regulatory regions surrounding the core of the gene that codes for the protein's amino acid sequence. “These regulatory regions determine when, how strongly, and in which cell a gene is switched on. Dysregulation of these sections can lead to protein overproduction, underproduction, or complete lack of protein production. Depending on the protein's role in the cell, these errors can have severe or benign consequences.”

Regulatory regions make up the largest part of our genome. Many relatively short DNA snippets lie scattered around the coding regions and act as on and off switches for genes. How this seemingly random arrangement of these regulatory elements leads to precise gene activity remains largely unknown. This is the “regulatory code” that Ibrahim and his team aim to decipher.

To understand how gene activity could be “programmed“ into DNA, Ibrahim and his colleagues want to edit the DNA of stem cells and analyze how this changes gene expression. “We have pinpoint accuracy in exchanging individual letters of DNA,” explains Ibrahim. “However, changing long sections of DNA is challenging, and that's precisely what we need to do to decipher the regulatory code. And this is where the ERC project comes in!”

Uncovering control mechanisms with synthetic DNA

To investigate the effects of such large-scale DNA modifications in a systematic manner, the researchers want to synthesize artificial DNA sequences in the lab. They then plan to introduce these large synthetic DNA fragments into the genome of mouse stem cells. In these synthetic sequences, the scientists will rearrange genetic on and off switches in various configurations aiming to selectively activate a fluorescent protein only in specific cell types. The results will reveal how well we understand the regulatory code, explains Ibrahim: “By observing which cells light up, we can judge our success in re-programming gene activity: Are exactly the right cell types active? Is the gene inactive in other cell types?”

From these observations, Daniel Ibrahim hopes to gain new insights into the genome's hidden information. “What role does the position or the distance between the regulatory elements play? How do multiple on and off switches influence each other?”