Failure in male sex cell development caused by a hijacking of genetic blueprint

CRM scientists have identified a fundamental molecular mechanism behind the failure in maintenance of male sex cells in two strains of genetically modified mice. The paper was published in Nature Structural & Molecular Biology.

The cells that will give rise to sperm cells (germ cells) are first produced very early in development. During germ cell development, these cells undergo a dramatic change in which they are genetically reprogrammed by a process of DNA demethylation followed by methylation. This process is known as germline reprogramming and is fundamental to development of fertile sperm in adulthood. 

The authors found a failure of the process of germline reprogramming and rewiring of the way genes are expressed as the mechanism leading to the loss of sperm producing cells (spermatogonia) in mice lacking either of two genes, Dnmt3l or Miwi2. This work could help understand certain kinds of infertility caused by loss of spermatogonia.  

The study team, led by CRM Associate Director Professor Dónal O’Carroll, used two strains of genetically modified mice each lacking a gene (Dnmt3l or Miwi2), both of which have a role in regulating a molecular modification of DNA (DNA methylation). These mice have previously been shown to show a progressive loss of all germ cells, but it was unclear whether this was caused by a failure of normal development of the germ cells or in maintaining spermatogonia in adults. 

The researchers looked at which genes were switched on in the spermatogonia from mutant mice by analysing the messenger RNA (mRNA), the molecule that decodes DNA to produce the proteins that make up cells. The profile of mRNAs present in a cell is called the transcriptome.

During normal germline development, a key component of germline reprogramming is methylation of a type of genes known as Transposable Elements (TEs), genetic material that can “jump” from one location in the DNA to another.

A deregulation of TEs can lead to DNA damage but the study found this was not the mechanism for the loss of spermatogonia. Analysis of the RNA expression showed that a family of TEs called the intracisternal-A particle (IAP) promoters were de-regulated. Further analysis showed that the IAP promoters drive the expression of neighbouring genes altering or “rewiring” the transcriptome. It is this deregulation of gene expression that leads to a loss of spermatogonia. 

The authors finally found a relationship between the location of abnormal methylation and the TEs, indicating that activation of the TEs is mediated by abnormal DNA methylation. 

This work highlights a new mechanism by which defective reprogramming and transposable elements can derail germ cell function 

Professor Dónal O’Carroll

This study was published in Nature Structural & Molecular Biology and was led by Professor Dónal O’Carroll in collaboration with colleagues at the Babraham Institute, Cambridge, UK and EMBO, Italy. This work was supported by funding from the European Research Council. 

Reference: Vasiliauskaitė, Berrens, Ivanova, Carrieri, Reik, Enright & O’Carroll. (2018). Defective germline reprogramming rewires the spermatogonial transcription. Nature Structural & Molecular Biology DOI: http://dx.doi.org/10.1038/s41594-018-0058-0