BLANC - Blanc

A functional network of imprinted genes: epigenetic control through higher-order chromatin architecture – EpiNet

Submission summary

Genomic imprinting is an epigenetic mechanism of gene regulation that restrains the expression of ~80 eutherian and metatherian mammalian genes to one parental allele. Presently, imprinting is understood as a mechanism aimed at controlling the amount of maternal resources allocated to the offspring from conception to weaning. It is however not known whether every imprinted gene is involved in this process, or whether some imprinted genes function in other unidentified physiological processes. Partner 1 (Laurent Journot) has recently shown the existence of an intricate network of imprinted genes based on a meta-analysis of microarray data. This subset of mouse imprinted genes is tightly co-regulated and comprises those imprinted genes known to control embryonic growth, as inferred from the phenotype of gain- or loss-of-function mouse mutants. These data indicate that these genes are members of a network of imprinted genes involved in the control of embryonic development. Partners 2 (Thierry Forné) and 3 (Luisa Dandolo) have been working on genomic imprinting for many years and our current interest is to understand how genomic imprinting can control a certain number of genes involved in embryonic growth. The aim of our partnership is to bring together different expertise in fields as diverse as embryology, microarrays and chromatin architecture. We propose to use two different experimental models: - An in vitro approach using cell cultures in which the myogenic and adipogenic differentiation can be induced in order to analyse the role of this network at the proliferation/differentiation transition. - An in vivo approach based on murine loss- and/or gain-of-function mutants. These models are used to unravel cis and trans acting mechanisms that mediate the coordinated expression of the imprinted genes within the network. The project will also allow gaining further insight into the biological function of the imprinted gene network at the cellular level. We are planning: 1. To investigate how this network of genes is co-ordinately regulated in different models, with a particular emphasis on myogenic and adipogenic differentiation. 2. To investigate the chromatin architecture underlying cis acting mechanisms at imprinted gene clusters. Using a microarray approach, we perform a large-scale identification of elements involved in gene regulation using the very recently described Chromosome Conformation Capture (3C) technique and genomic MAR assays. Because of our expertise, we are initiating these experiments at two imprinted loci of the network: the H19/Igf2 and Dlk1/Gtl2 loci. 3. And finally to investigate the mechanisms involved in trans coordination of the network by focusing on the functions of two genes for which partners in this proposal are leading experts: the Zac1 gene and the H19 RNA. These trans regulations will be analysed in vitro and in our available mouse mutant models.

Project coordination

Laurent Journot (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 500,000 euros
Beginning and duration of the scientific project: - 36 Months

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