Blanc SVSE 2 - Sciences de la vie, de la santé et des écosystèmes : Biologie cellulaire, développement

Molecular and biological roles of the imprinted miR-379-miR-410 cluster – ImpMir

miRNAs and parental genomic imprinting

Through the use of a KO mouse model, our research programme aims at elucidating the biological roles of many imprinted miRNA genes

Biological roles of imprinted microRNA genes

miRNAs are endogenously expressed short non-coding RNAs that silence gene expression mostly at the post-transcriptional level. In animals, most miRNAs bind to mRNAs via short, imperfect base-pairing interactions that occur preferentially within the 3’ untranslated regions (UTRs) of target mRNAs. Through still poorly understood mechanisms, miRNA binding promotes silencing of the target mRNA by inhibiting its translation and/or by accelerating its degradation.<br /><br />miRNAs are now considered as potent posttranscriptional regulators in an ever-growing list of developmental, physiological or pathological contexts. However, we still need to determine precisely, at the whole-organism level, the extent to which defects in miRNA-mediated regulation yield clear and interpretable phenotypic consequences, especially in mammalian systems for which knockout (KO) mouse studies are just emerging.<br /><br />Our research program concerns many miRNAs that are only found in placental mammals and whose expression is controlled by genomic imprinting, an epigenetic mechanism that causes mono-allelic expression in a parent-of-origin dependent manner, e.g. for a given gene, only one of the two parental alleles is transcriptionally competent<br />

Through the use of knock-out mouse model, our project aims at elucidating the biological roles of many microRNAs: the so-called miR-379/miR-410 cluster. In other words, we are studying the molecular, cellular and physiological consequences of the genetic ablation of the miR-379/miR-410 cluster at the whole organismal level. This was achieved by deleting, in a sequence-specific manner, the entire miRNA cluster via the use of the Cre-LoxP system.

Our unpublished data show that the miR-379/miR-410 cluster plays essential roles in neonatal survival, notably by controlling metabolic adaptation to extra-uterine life.

Our data demonstrate that poorly conserved miRNA genes (only found in placental mammals) plays pivotal roles in neonatal survival. From an evolutionary perspective, we speculate that recent acquisition of the miR-379/miR410 cluster may have increased neonate fitness by improving their metabolic adaptability upon profound changes in nutrition. If so, this may have contributed to placental mammal evolution.

1- Labialle, S., and Cavaillé, J. (2011). Do repeated arrays of regulatory small-RNA genes elicit genomic imprinting? BioEssays 33, 565-573.
2- Girardot M, Cavaillé J and Feil R (2012). Small regulatory RNAs controlled by genomic imprinting and their contribution to human disease. Epigenetics. 2012 Dec 1;7(12):1341-8.
3- Labialle et al (2013) soumis pour publication.

Our current research interest is at the interface of two hot topics: (i) the expanding world of small regulatory RNAs (microRNAs) and (ii) the epigenetic regulation of eukaryotic gene expression (genomic imprinting).

Genomic imprinting is an intriguing epigenetic regulation of chromatin that violates classical Mendelian inheritance rules, since it leads to mono-allelic expression in a parent-of-origin specific manner. In other words, for a given gene-locus the paternal allele is turned on while the maternal allele, that can be genetically-identical, is turned off (the converse can also be true for another gene locus). Only a limited number of imprinted genes has been documented so far (n~ 80), mostly in eutherians (mammals with placenta) with many of them playing important roles in the regulation of fetal/placental growth and higher brain functions (behaviour). Functional importance of imprinted genes is proven given that their misregulation is associated with important developmental disorders in embryonic and/or placenta growth, in higher brain function as well as in cancers.

microRNAs are short antisense noncoding RNAs (~19-23 nt in length) that mainly act as post-transcriptional regulators of gene expression via short, imperfect base-pairing interactions, usually in the 3’-untranslated region (UTR) of mRNAs, either by blocking the translation and/or by accelerating the degradation of targeted mRNAs. By their ability to interact with a huge number of mRNAs, miRNA-mediated gene regulation is believed to exert important regulatory roles in a myriad of developmental and physiological situations, including cell proliferation, apoptosis, differentiation, developmental patterning. Nevertheless one must admit that we still need to precisely determine, in biologically relevant conditions, the physiological relevance of miRNA-mediated regulation, especially in mammals for which loss-of-function studies are just beginning.

Our most recent results indicate that an unexpected large proportion of microRNA (20-25% of human/mouse microRNA genes, respectively) is associated with imprinted chromosomal domains, with more than 90% of them organized into large clusters of related microRNA, thus pointing to a functional and/or evolutionary link between epigenetic regulation and RNA silencing. Our multidisciplinary programme concerns a large cluster of maternally-expressed microRNA genes (~ 40-50), namely the miR-379-miR-410 cluster at the Dlk1-Dio3 domain that accounts fro 10% of mouse microRNAs. In the adult, this cluster is mostly, if not exclusively expressed in the brain (neuronal expression). Interestingly, recent data from the literature point to their potential involvement in dendritogenesis as well as synapse plasticity.

Our interdisciplinary project concerns the study of a KO mouse model in which the mir-379-miR-410 was removed through Cre-LoxP mediated, site-specific recombination. This project represents unique opportunities to fully appreciate the biological function of microRNAs in mammals and thus to decipher their mode of action and impact on transcriptome and proteome outputs. There is no doubt that our fundamental project will have repercussions in the biomedical field, particularly for brain diseases and also very likely for cancers.

Project coordination


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.



Help of the ANR 361,407 euros
Beginning and duration of the scientific project: - 36 Months

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