Genetics and epigenetics of germinal differentiation


mediated growth acceleration and twin formation is observed with microinjection of miR-124 into the fertilized eggs. Photo shows duplication of the egg cylinder visible at 7.5 days embryos.

It is now common observation that, in spite of the analytical power and extensive validity of the Mendelian analysis, a number of observations are still not explained by mutation/segregation of genes or combinations of genes. Epidemiology failed to identify determinants for a number of familial pathologies and the same is true of the heritability of characters such as body height, even with all the power of the present-day genomic technologies. Unknown, non-Mendelian modes of heredity have therefore been considered, resulting in the transmission of epigenetic variations that modulate the expression of genes. This mode of inheritance was described more than 50 years ago in plants under the name 'paramutation' but its applicability to the animal and human models appeared for a long time doubtful.

We then reported (Rassoulzadegan et al., Nature, 2006, 441:469) the first instance of non-Mendelian inheritance of an epigenetic variation in the mouse that we designated 'paramutation' in spite of significant differences with the plant phenomenon. The initial observations were on a convenient color variation (the traditional tool of the geneticist) and they were subsequently extended to a case of heart malformation, a model of a serious, often fatal pathology in human and to a spectacular variation in embryonic growth and body size resulting in gigantism and gemellity (Wagner et al., Dev Cell, 2008, 14:962; Granjean et al., Development, 2009, 136:3647). In all three cases, the determinant epigenetic controls were exerted by non coding RNAs, either RNA fragments of the regular transcript or the cognate microRNAs. They modulate respectively the transcriptional activity of Kit, Cdk9 and Sox9. Transfer of RNA by the gamete, sperm RNA in the case of paternal transmission, was shown to be responsible for inheritance.

Our current activity includes a search for the possible occurrence of such epigenetic variation at other loci, defining a class of 'paramutable genes'. We are developing the analysis of the molecular mechanisms remodeling the local chromatin structures of established variant states, their maintenance and hereditary transmission. The role of RNA molecules carried by the spermatozoon to the ovocyte, transgenerational vectors of the epigenetic information, is analyzed. We have shown that their transfer into embryonic stem cells (ES) and differentiated cells in culture induces the modifications, providing us with experimental systems more amenable to the molecular analysis than the early embryo for the analysis of the epigenetic events induced by RNAs, including paramutation and a variety of programmations.

Two projects are concerned with a distinct class of developmental epigenetic controls directing the conversion of the ovocyte into the first pluripotent stem cell. One aspect is the reprogrammation of a somatic cell in a pluripotent stem cell. It is known from the work of Yamanaka and his followers to be achieved by the expression of four genes from transfected vectors. Events described as 'mysterious' by the authors themselves then result in the epigenetic activation of the key determinants of pluripotency Nanog and Oct4, while the transfected constructs are silenced. A paramutation like phenomenon may be at play, induced by the initial accumulation of RNAs from the transfected vectors. Encouraged by promising exploratory results, we will develop strategies for RNA-based reprogrammation.

Our most recent project starts from the discovery made by deep sequencing of the sperm RNA component of two small molecules conserved from mouse to man and exclusively present in mature sperm. In the embryo, both remain stably associated with the nucleus through all the pluripotent stages. Their functions are analyzed by biochemical and genetic means and we are led to consider a general role of 'spermatozoal RNAs' in the early developmental period.

 

Last publications

RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. - 2006 - Nature - 441 P469-74 - Rassoulzadegan M, Grandjean V, Gounon P, Vincent S, Gillot I, and Cuzin,F

The spermatogonial stem cell: from basic knowledge to transgenic technology. - 2005 - Int J Biochem Cell Biol - 37 P246-50 - Olive V, and Cuzin, F

Primary spermatocyte-specific Cre recombinase activity in transgenic mice. - 2004 - Transgenic Res - 13 P289-94 - Chung SS, Cuzin F, Rassoulzadegan M, and Wolgemuth, DJ

[Germ stem cells: from basic knowledge to their use in gene transfer] - 2004 - Med Sci (Paris) - 19 P653-6 - Cuzin F, and Rassoulzadegan, M

A novel germ line-specific gene of the phosducin-like protein (PhLP) family. A meiotic function conserved from yeast to mice. - 2003 - J Biol Chem - 278 P1751-7 - Lopez P, Yaman R, Lopez-Fernandez LA, Vidal F, Puel D, Clertant P, Cuzin F, and Rassoulzadegan, M

Transvection effects involving DNA methylation during meiosis in the mouse. - 2002 - EMBO J - 21 P440-50 - Rassoulzadegan M, Magliano M, and Cuzin, F

Murine spermatogonial stem cells: targeted transgene expression and purification in an active state. - 2002 - EMBO Rep - 3 P753-9 - Giuili G, Tomljenovic A, Labrecque N, Oulad-Abdelghani M, Rassoulzadegan M, and Cuzin, F

Gene control in germinal differentiation: RNF6, a transcription regulatory protein in the mouse sertoli cell. - 2002 - Mol Cell Biol - 22 P3488-96 - Lopez P, Vidal F, Martin L, Lopez-Fernandez LA, Rual JF, Rosen BS, Cuzin F, and Rassoulzadegan, M

Gene trap analysis of germ cell signaling to Sertoli cells: NGF-TrkA mediated induction of Fra1 and Fos by post-meiotic germ cells. - 2001 - J Cell Sci - 114 P435-43 - Vidal F, Lopez P, Lopez-Fernandez LA, Ranc F, Scimeca JC, Cuzin F, and Rassoulzadegan, M

Phagocytosis reveals a reversible differentiated state early in the development of the mouse embryo. - 2000 - EMBO J - 19 P3295-303 - Rassoulzadegan M, Rosen BS, Gillot I, and Cuzin, F

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Rassoulzadegan Minoo
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   Cuzin François
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    October 2013 - Rassoulzadegan Minoo Team
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