A systems-level approach to parental genomic imprinting: the imprinted gene network includes extracellular matrix genes and regulates cell cycle exit and differentiation.

Hala Al Adhami,Laurent Journot,Christelle Dantec,Tristan Bouschet,Hugues Parrinello,Anne Le Digarcher,Charlotte Gueydan,Annie Varrault,Emeric Dubois,Brendan Evano

doi:10.1101/gr.175919.114

Abstract

Genomic imprinting is an epigenetic mechanism that restrains the expression of ∼100 eutherian genes in a parent-of-origin-specific manner. The reason for this selective targeting of genes with seemingly disparate molecular functions is unclear. In the present work, we show that imprinted genes are coexpressed in a network that is regulated at the transition from proliferation to quiescence and differentiation during fibroblast cell cycle withdrawal, adipogenesis in vitro, and muscle regeneration in vivo. Imprinted gene regulation is not linked to alteration of DNA methylation or to perturbation of monoallelic, parent-of-origin-dependent expression. Overexpression and knockdown of imprinted gene expression alters the sensitivity of preadipocytes to contact inhibition and adipogenic differentiation. In silico and in cellulo experiments showed that the imprinted gene network includes biallelically expressed, nonimprinted genes. These control the extracellular matrix composition, cell adhesion, cell junction, and extracellular matrix-activated and growth factor–activated signaling. These observations show that imprinted genes share a common biological process that may account for their seemingly diverse roles in embryonic development, obesity, diabetes, muscle physiology, and neoplasm.

Highlights

Genomic imprinting is an epigenetic phenomenon that leads to a parent-of-origin-specific expression of alleles in metatherian and eutherian mammals (Ferguson-Smith 2011)
The present work extended this discovery and showed that most imprinted genes (IGs) belonged to a single gene network that comprised biallelically expressed genes involved in the control of the extracellular matrix (ECM) composition, cell adhesion, and cell–cell contacts
We showed that the network of 85 IGs was topologically different to 10,000 networks obtained by randomly drawing sets of 85 genes with data in COXPRESdb (Fig. 1B)

Summary

Introduction

Genomic imprinting is an epigenetic phenomenon that leads to a parent-of-origin-specific expression of alleles in metatherian and eutherian mammals (Ferguson-Smith 2011). The type of epigenetic marks, how they are established at specific loci during gametogenesis, and how they are maintained after fertilization, as well as the mechanisms leading to monoallelic expression, are understood for several IGs (Bartolomei and Ferguson-Smith 2011; Kelsey and Feil 2013). Pronuclear transplantation experiments (McGrath and Solter 1984; Surani et al 1984), the analysis of the phenotype of mouse strains carrying uniparental disomy of various chromosomes or uniparental duplication of various chromosomal regions (Cattanach and Kirk 1985; Cattanach et al 2006), and the phenotypic characterization of targeted mouse mutants led to the suggestion that IGs are key regulators of embryonic development (Ferguson-Smith 2011). Molecular functions associated with IGs are diverse and include signaling, ion channel, nutrient transport, transcription factor, noncoding RNA, extracellular matrix (ECM) protein, control of cell cycle, metabolism, protein synthesis, protein degradation, and vesicular secretion.

Methods

Results

Conclusion