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Dissecting the gene regulatory mechanisms that generate serotonergic neurons and their link to mental disorders

Final Report Summary - SEROTONINANDDISEASE (Dissecting the gene regulatory mechanisms that generate serotonergic neurons and their link to mental disorders)

All cells in the body essentially share the same DNA (genome), despite looking very different and playing a range of roles. The reason that cell types are so different from one another is because of the way they interpret the genome. Each different type of cell uses a specific subset of the genes within the genome. The part of the DNA that controls which cell will use which genes and when is called the regulatory genome; this DNA is not translated into proteins.
The regulatory genome is much less well understood than the protein-coding genome. At present, when a new species is discovered, it is often possible to sequence its DNA and deduce where the protein-coding genes are and what roles they might play. However, it is not yet possible to do the same for the regulatory genome. Finding a way to do this is an important step towards understanding when and where each of the organism’s genes is active.
In this project we focused on the regulatory genome of nerve cells that synthesize and use a chemical messenger called serotonin. They regulate multiple processes and their dysfunction has been linked to bipolar disorder, depression, anxiety, anorexia and schizophrenia. Importantly, serotonergic neurons are present in all eumetazoan groups thus we took advantage of the simplicity and amenability of the nematode worm Caenorhabditis elegans to study the genetic program directing serotonergic specification.
We have identified a set of TFs that work together, as a TF collective, to select the genes of the genome required for serotonergic neuron function. Our work is a small step towards understanding how the regulatory genome works. Comparisons with similar nerve cells from mammals found that the equivalent transcription factors have the same role, suggesting that they may be broadly conserved across species. Understanding the regulatory genome better could eventually lead to new treatments for certain genetic conditions, as many mutations associated with diseases appear outside the protein-coding genome.