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UniProt release 2017_07

Published July 5, 2017


A pseudogene turns into an active DNA methyltransferase dedicated to male fertility

It is well established that in mammals, the DNA methylation machinery is composed of 3 DNA methyltransferase (DNMT) enzymes, DNMT1, DNMT3A, and DNMT3B, and one catalytically inactive cofactor, DNMT3L. Some 46 million years ago, in the last common ancestor of the muroid rodents, the DNMT3B gene was duplicated, giving rise to Gm14490. The genes share about 70% identity, but Gm14490 underwent pseudogenization, and there is no evidence for its transcription. Germline-specific knockouts of DNMT3A or DNMT3B demonstrate the crucial role of these genes in methylation of most imprinted loci in germ cells (and somatic tissues), but some transposon loci, such as minor satellite DNA and intracisternal A particle (IAP) repeats, are only minimally affected, an observation which can be attributed to the functional redundancy of the 2 genes. This is what was thought and published, until recently.

Retrotransposon silencing is of paramount importance, especially in the male germline. Indeed, in the absence of silencing, retrotransposon reactivation leads inexorably to meiotic failure, azoospermia, and sterility marked by small testis size, a phenotype called hypogonadism. It is therefore essential to understand which actors are involved in this process. Barau et al. tackled the issue by generating mutant mice through N-ethyl-N-nitrosourea (ENU) mutagenesis and screening hypogonadal male mice for ectopic retrotransposon activity, followed by whole genome sequencing to identify the culprits. This approach led to the discovery of an ENU-independent mutation, which was identified as a de novo IAP insertion located in an unexpected locus, the last intron of the Gm14490 pseudogene. Serendipity definitely is a scientist’s best friend!

This was only the beginning of surprises. Contrary to what had been previously reported, the Gm14490 gene proved to be expressed, but exclusively in male germ cells. This restriction could explain the absence of corresponding ESTs in databases and the erroneous former assumption that it was untranscribed. During embryonic development, its expression peaks at the time of de novo DNA methylation (between 16.5 to 18.5 dpc) in prospermatogonia. Moreover, Gm14490 appeared to be catalytically active when transfected in ES cells. A new genuine DNA methylase was born and renamed DNMT3C!

In the absence of DNMT3C, either by knockout or by IAP insertion, retrotransposons, and more specifically some types of long interspersed nuclear elements (LINEs) and some endogenous retroviruses (ERV), are reactivated. Interestingly, this reactivation is particularly strong for evolutionarily ‘young’ subfamilies, indicating DNMT3C’s unique selectivity. The existence of a 5th DNA methylase selectively targeted at young retrotransposons, acting only in the context of fetal spermatogenesis, may be of particular relevance in Muroidea, including mice and rats. This lineage is particularly enriched in young transposons with about 25% that have integrated into the genome in the last 25 million years with currently thousands of active copies. In comparison, in the primate ancestor, massive integration occurred long before (80 million years ago for elements such as LINEs) and these transposons have since become extinct.

In view of these results, DNMT3C has been deleted from our pseudogene list, annotated and integrated into UniProtKB/Swiss-Prot, where it is available to you. The knowledgebase contains some other sequences derived from putative pseudogenes (see headline of November 2009). Like all other UniProtKB/Swiss-Prot entries, they are continuously reviewed. Some of them are deleted from UniProtKB, when data pointing at an inactive gene are overwhelming, but they can always be retrieved from UniParc. Other entries are progressively ‘upgraded’, when new data become available, to bona fide proteins as was the case for DNMT3C.

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