Step-by-step: prevent sabotage
Safeguarding the next generation’s genome
We may not notice it, but our genomes are under constant threat from internal saboteurs: sequences of DNA called transposons – or jumping genes – which are able to copy and paste themselves from one part of the genome to another. Dónal O’Carroll’s group at EMBL Monterotondo has been studying just how our cells keep these genomic saboteurs at bay. Recently, working with Anton Enright’s group at EMBL-EBI and Vladimir Benes’ Genomics Core Facility in Heidelberg, Dónal and his group have discovered another major piece of the puzzle.
They found that, as a mouse’s sperm cells are formed, they keep their transposons in check through a combination of different tactics. Chemical tags called methyl groups are deployed in two stages, first locking directly onto the DNA and later locking onto histones – the proteins around which DNA wraps itself. And when the sperm cell is almost formed, a group of molecules collectively called the piRNA pathway cut up any rogue transposons that could pose a threat to the genome of the next generation.
EMBL Explore podcast: Jumping genes
Di Giacomo, M., Comazzetto, S., Saini, H., De Fazio, S., Carrieri, C., Morgan, M., Vasiliauskaite, L., Benes, V., Enright, A.J., & O’Carroll, D. Multiple epigenetic mechanisms and the piRNA pathway enforce LINE1 silencing during adult spermatogenesis. Molecular Cell, 23 May 2013 (Vol. 50, Issue 4, pp. 601-608). DOI: 10.1016/j.molcel.2013.04.026.
Transposons present an acute challenge to the germline, and mechanisms that repress their activity are essential for transgenerational genomic integrity. LINE1 (L1) is the most successful retrotransposon and is epigenetically repressed by CpG DNA methylation. Here, we identify two additional important mechanisms by which L1 is repressed during spermatogenesis. We demonstrate that the Piwi protein Mili and the piRNA pathway are required to posttranscriptionally silence L1 in meiotic pachytene cells even in the presence of normal L1 DNA methylation. Strikingly, in the absence of both a functional piRNA pathway and DNA methylation, L1 elements are normally repressed in mitotic stages of spermatogenesis. Accordingly, we find that the euchromatic repressive histone H3 dimethylated lysine 9 modification cosuppresses L1 expression therein. We demonstrate the existence of multiple epigenetic mechanisms that in conjunction with the piRNA pathway sequentially enforce L1 silencing and genomic stability during mitotic and meiotic stages of adult spermatogenesis.