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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?”

A potential path to new gene therapies

In addition to advancing our scientific understanding of gene regulation, the technologies that will be developed within Daniel Ibrahim's project could have significant medical applications. They could potentially pave the way for the development of new gene therapies that involve replacing or introducing larger segments of genetic material.

Currently, gene therapy typically involves inserting relatively short pieces of DNA into a patient's cells, where they are incorporated into the genome. While the CRISPR/Cas9 method can modify DNA with extreme precision, it can still only replace relatively short sections, limiting the potential of gene therapy.

“Some colleagues at BIH are working on gene therapies, which require introducing longer sections of DNA, and they are very interested in applying our new technologies to more clinical settings,” says Ibrahim. “This is where we would love to help. Then research could actually become health.”

About the ERC Starting Grant

The reviewers of the European Research Council are looking for unusual approaches that potentially could enable significant progress (a “high risk, high reward” approach). Candidates must have two to seven years of experience since obtaining their doctorate and must have demonstrated promising scientific achievements. Grant Agreement No. 101076709

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