Professor Brickman awarded grant by the European Research Council

Principal investigator and professor Joshua Brickman from the Novo Nordisk Foundation for Stem Cell Medicine, reNEW

The European Research Council (ERC) has awarded Professor Joshua Brickman and his team a 2.5 million euro grant for their work on the key role held by transcription factors in genes and how they interact with the relay system found in a cell. The grant is awarded for a period of five years.

“This grant is a great boon to our ongoing research on the crucial role of transcription factors in plasticity and regeneration. We focus on exploring the interaction of transcription factors with the signaling relay systems inside cells to understand how they communicate instructions and accesses the information residing in their genomes,” said Professor Joshua Brickman at reNEW’s Copenhagen node.

What is a transcription factor?
Transcription factors are proteins that govern the identity of a cell: how it becomes specialized as the embryo develops into a human being or how stem cells make organs. Since the early days of molecular biology, how transcription factors turn on and off genes and how the sections of DNA they are recruited to, enhancers, identify and turn on different genes has remained a mystery. Since the 80’s, it was assumed that when an enhancer recruited a transcription factor it would turn its gene on.

Recent research carried out by Brickman and his team suggests that this is not the case. They recently found that some transcription factors remain associated with their enhancers in differentiation, sitting there without turning the gene on, but preserving the ability of a cell to change its mind or turn back on stem cell genes after its begun to differentiate or develop. They also found that transcription factors sit on specialized genes in stem cells, do not turn them on, but establish their potential to be turned on as the cell differentiates.

The image shows the remarkable regenerative and regulative properties of the mammalian embryo. One the left a normal mouse embryo, and on the right, a large embryo formed by sticking two embryos together. Here, cells have changed their direction in differentiation and adopted new fates, to form a perfectly proportioned but larger embryo. SENCE seeks to understand how transcription factor persistence supports the competence for this plasticity and how it relates to regeneration. Photo by a PhD student in the Brickman Lab, Marta Perera Pérez.

Relay systems turn genes on
So, what is it that turn genes on? It’s the relay system that is used by cells to interpret signals from other cells. In a complex organism, different cells produce chemical signals to communicate instructions to other cells. The receiving cells then use a molecular relay system to transmit this information from the cell surface to the DNA in the nucleus.

Brickman and his team’s research focus on this relay system. They have developed technology to activate this relay system in every cell in the dish and isolate the role played by the relay and the transcription factor. The ERC grant will enable them to exploit this technology and explore the generality of these new paradigms for gene regulation.

Research on the interaction between the transcription factors and relay system
Using this new funding, Brickman and his team try to figure out how the relay system finds the right transcription factors to work with and turn the right genes on or off. They will exploit their ability to activate the relay system to understand how transcription factors act from gene enhancers, how transcription factors protect past and future cell identities, and how enhancers act with the relay system/transcription factors to activate the correct genes from far away in their genome.

Finally the researchers want to understand how transcription factors support plasticity in early development and cell differentiation. The mammalian embryo is remarkable. It can twin, single embryos can be split in half to form two normal embryos, or two embryos can be put together to make one very large one. This plasticity is the reason pregestational diagnosis is possible, as the missing cells are replaced by other cells that transform themselves into the missing cell type.

Based on their discovery of what transcription factors do in stem cells, Brickman and his team have hypothesized that the persistence of a select set of them endows cells with the ability to change their mind and hence regenerate missing tissue. They want to understand how the cells do this.

Reprogrammed neurons may fool you!

Associate Professor Agnete Kirkeby, from reNEW Copenhagen, has published the paper Forced LMX1A expression induces dorsal neural fates and disrupts patterning of human embryonic stem cells into ventral midbrain dopaminergic neurons, in Stem Cell Reports.