Epigenetic Decisions and Reproduction in Mammals

The interest of our team is focused on understanding the nature and the role of the epigenetic information within the peri-conception window, which encompasses gametogenesis, fertilization and early embryonic development.

Figure 1 : Expression analysis 
by RNA-seq of different classes of
transposons in testes of Dnmt3L
-/- mice at different ages post-
partum.

Our efforts are mostly centered on DNA methylation, how it influences gametic production and integrity, and impacts on phenotypes at following generations. Our approach is mainly fundamental, using the mouse as a mammalian model. We are also extending our knowledge to human through collaborations with fertility centers.

Studying the epigenetic setting of germ cells allows investigating several crucial aspects of mammalian biology such as transposon control, genomic imprinting and early lineage commitment. Studying DNA methylation in the window of conception leads also to mechanistic insights into the spatio-temporal control of genomic methylation specificity, including components of histone modification and RNA-directed pathways (small and long). Our work extends over these different aspects, through the use of fine developmental and molecular dissection, combined with genetic tools (CRISPR) and genome-wide sequencing approaches.

Our work can be subdivided in three themes related to the role of epigenetics in mammalian reproduction.

Figure 2: Germ cells (blue) undergoing de novo DNA methylation. Left: fetal testis, right: adult ovary.

1. The first focuses on the protection of the male germ line against transposons. These genetic parasites make up the majority of the mammalian genomes and can impact on genome architecture and function in a variety of ways. We are investigating the cellular and genetic damages that transposons can inflict on the male germ line, as well as the cooperation of different levels of transposon control, including specialized small interfering RNAs. This aspect is developed mostly in the mouse model, but we are also investigating transposon regulation during normal human spermatogenesis and in germ cell tumors.
2. The second aspect deals with the importance of epigenetic processes in the female germ line. Oocyte methylation is particularly involved in the control of parent-specific expression of imprinted genes. We have been developing a genome-wide methylation screening for the identification of new imprinted genes, and are investigating the mechanisms underlying imprinted regulation. We are also screening for new targets of oocyte methylation, and in particular for genes that are epigenetically programmed in the oocyte for their participation to the first lineage decision after fertilization.
3. Finally, we are investigating the mechanisms underlying the acquisition of DNA methylation patterns, in an attempt to identify the positive and negative drivers of DNA methylation. We are using biologically relevant in vivo material, such as germ cells and early embryos, but are also developing cellular models of DNA methylation switch.

Correct DNA methylation patterns are paramount for the generation of functional gametes capable of forming viable offspring, but also for the regulation of pluripotency states and the maintenance of genome architecture and expression in somatic cells. Our work, not only impacts on the field of reproduction and development, but also on stem cell biology and cancer.