Understanding the role of epigenetics in male fertility

DNA methylation is an essential epigenetic marker for fertility. It is during fetal life that the sperm precursor cells, which produce these male gametes throughout the reproductive life of a male, acquire the DNA methylation markers that characterize their identity.

These markers depend on enzymes, DNA methyltransferases, such as DNMT3A and DNMT3C, whose crucial role in spermatogenesis has just been demonstrated by the Epigenetic Decisions and Reproduction in Mammals team at Institut Curie, led by Déborah Bourc'his, in the Genetics and Developmental Biology unit (Institut Curie, CNRS, Inserm, Sorbonne University). These biologists had already identified the action of DNMT3C on retrotransposons, which are mobile elements responsible for instability in the genome.

DNMT3C makes sure that the retrotransposons do not interfere with meiosis, the cell division that produces gametes.” But we knew nothing about the role of the other enzyme, DNMT3A.

Explains Déborah Bourc'his.

We showed that these two enzymes had a complementary and non-redundant role on sperm precursor methylation,

Explains the team leader.

In their latest article published in Nature Genetics, the biologists used a mouse model to show that DNMT3A controls the expression of stem cell genes.

It thus balances the dual ability of stem cells to self-renew and engage in spermatogenesis. Without the methylation established by DNMT3A, they remain locked in their role as stem cells, without ever producing spermatozoa

Says Déborah Bourc'his.

To demonstrate this, biologists studied the genes expressed in stem cells with and without DNMT3A in animals, cell by cell. "Sperm development is based on a subtle hierarchy of different cells. To distinguish between them, single-cell analysis was essential," explains this epigenetics specialist.

This work generates a number of questions. “DNMT3A is expressed in the stem cells of other organs. Does the methylation it deposits have the same role in regulating their function in these tissues?”, asks Déborah Bourc’his. It will also be important to determine how these phenomena manifest themselves in human cells. In the meantime, this work provides a better understanding of the role of epigenetics in spermatogenesis, which will shed light on the origin of certain infertilities but also of rare testicular cancers, seminomas, which develop from the precursors of spermatozoa.