Keys to the genome: a step towards greater understanding

Keys to the genome: a step towards greater understanding

The laboratory of Dr. Jacques Drouin, Director of the Molecular Genetics Research Unit at the Montreal Clinical Research Institute (IRCM), has just discovered the molecular mechanisms responsible for opening up the genome and expressing new genes, an important step towards understanding the mechanisms underlying the genome.

This opening is achieved by so-called pioneer transcription factors that open the chromatin packaging of the genome to allow the expression of previously inaccessible genes. Chromatin opening is a fundamental epigenetic regulatory process involving multiple steps identified in the Drouin laboratory's recent publication in Nature Structural & Molecular Biology. The action of pioneer factors is essential for the establishment of new cell fates during the development of complex organisms.

"Pioneer factors are the master regulators of the genome and epigenome: any disruption of their action has major consequences," emphasized Dr. Drouin, who is also a Full Professor in the Department of Biochemistry at the Université de Montréal.

Why is it important ?
Understanding the mechanism of action of pioneers is important because these factors are essential for reprogramming cell identity for therapeutic purposes such as cellular treatments for diabetes or Parkinson's disease. In addition, many cancers are caused by disruption of pioneer action: their mechanism of action is therefore a target for new therapeutic approaches.

A laboratory fertile with scientific advances
Controlled gene expression is essential for the development of complex organisms. This expression is the implementation of the plan encoded in our genome, and its deregulation, whether due to mutations or epigenetic perturbations, causes congenital malformations, more or less severe deficits and cancer. The Molecular Genetics Research Unit studies these mechanisms, from their basic principles to their application in human health. In particular, Jacques Drouin's team has discovered new regulators of gene expression, such as the Pitx subfamily, that controls development of the pituitary gland and craniofacial structures (Pitx1), the identity of legs compared to arms (Pitx1), left-right asymmetry (Pitx2), muscle development (Pitx2 and Pitx3) and the survival of dopaminergic neurons that degenerate in Parkinson's disease (Pitx3). In recent years, the group has made important contributions to the mechanism of action of pioneering factors that remodel the epigenome for cell fate specification.

The work of the Drouin team is funded by the Canadian Institutes of Health Research (CIHR) and Calcul Québec (Digital Research Alliance of Canada).

Gouhier A, Dumoulin-Gagnon J, Lapointe-Roberge V, Harris J, Balsalobre A, Drouin J, Pioneer factor Pax7 initiates two-step cell-cycle dependent chromatin opening, Nature Structural & Molecular Biology, 2024;31(1):92-101. doi: 10.1038/s41594-023-01152-y.

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