Laurent Journot

Introduction

Parental genomic imprinting restrains the expression of about 150 genes in eutherian mammals to one allele according to its parental origin. The alteration of genomic imprinting at defined loci results in different syndromes with complex phenotypes: Angelman, Beckwith-Wiedemann, Prader-Willi, Silver-Russel, and Transient Neonatal Diabetes Mellitus (TNDM). In addition, a number of imprinted genes are involved in tumor formation as oncogenes or tumor suppressor genes.

The present research on genomic imprinting is focusing on 3 main questions:

• What selective advantage is given by the implementation of parental genomic imprinting during mammalian evolution, at the transition from prototherian to metatherian?
• What molecular mechanisms are involved in differential marking of paternal and maternal alleles during gametogenesis? How do these marks lead to mono-allelic expression of the targeted genes?
• What is special with respect to imprinted gene function that may explain why these genes were targeted by a specific mechanism of gene regulation?

Laurent Journot and his group address the latter question, with a special emphasis on one of the imprinted genes, Zac1/Plagl1, the TNDM gene.

Projects

Imprinted genes are seemingly functionally unrelated; they do not belong to a single gene family or signaling pathway, nor do they work in an identified biological process. Accordingly, the reason for the selective targeting by genomic imprinting of a limited subset of genes with disparate molecular functions during mammalian evolution is unclear.

One current hypothesis with respect to imprinted gene function is they affect the metabolic homeostasis at the organismal level by controlling independently the metabolism of different organs including muscle, liver, pancreas, adipose tissue… The alternative hypothesis explored by Laurent Journot and his team is that imprinted genes cooperate in a single biological process that remains to be identified.

To analyze the function of imprinted genes Laurent Journot and his group combine genome-wide genomic and epigenomic techniques, in vitro cell culture, the characterization of mouse mutants, computational biology, and bio-statistics. They develop a cellular model for TNDM from human induced pluripotent stem cells and study the impact of imprinted gene mutation on normal developmental processes such as corticogenesis, adipogenesis, and pancreatic beta cell differentiation. They also study the impact of imprinted gene mutation in preclinical models of tumorigenesis.

Impact

Understanding the function of imprinted genes during normal development is crucial to identify the biological process that was targeted by parental genomic imprinting during mammalian evolution. It will also help understanding the processes that are altered in imprinted disorders and in tumors with gain or loss of imprinted gene function.