rahu is a mutant allele of Dnmt3c, encoding a DNA methyltransferase homolog required for meiosis and transposon repression in the mouse male germline

Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs-Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l-that establish and maintain cytosine-5 methylation. Here we ident...

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Bibliographic Details
Published in:PLoS genetics 2017-08, Vol.13 (8), p.e1006964-e1006964
Main Authors: Jain, Devanshi, Meydan, Cem, Lange, Julian, Claeys Bouuaert, Corentin, Lailler, Nathalie, Mason, Christopher E, Anderson, Kathryn V, Keeney, Scott
Format: Article
Language:English
Subjects:
Alleles
Amino Acid Sequence
Animals
Bioinformatics
Biology and life sciences
Biophysics
Cancer
Chromosome Mapping
Consortia
Cytosine
Deoxyribonucleic acid
Dimerization
Divergence
DNA
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA Breaks, Double-Stranded
DNA methylation
DNA Methylation - genetics
DNA methyltransferase
DNA Repair
DNMT1 protein
Epigenetic Repression
Epigenetics
Funding
Gene expression
Gene silencing
Genomes
Germ Cells - cytology
Germ Cells - metabolism
Homology
Immunodeficiency
Infertility, Male - genetics
Male
Mammals
Medical research
Meiosis
Meiosis - genetics
Mice
Mice, Inbred C57BL
Molecular biology
Mutation
Phylogeny
Physiology
Protein Conformation
Proteins
Research and Analysis Methods
Retroelements - genetics
Sequence Analysis, RNA
Sexual reproduction
Specialization
Sterility
Supervision
Transposons
Up-Regulation
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Summary:Transcriptional silencing by heritable cytosine-5 methylation is an ancient strategy to repress transposable elements. It was previously thought that mammals possess four DNA methyltransferase paralogs-Dnmt1, Dnmt3a, Dnmt3b and Dnmt3l-that establish and maintain cytosine-5 methylation. Here we identify a fifth paralog, Dnmt3c, that is essential for retrotransposon methylation and repression in the mouse male germline. From a phenotype-based forward genetics screen, we isolated a mutant mouse called 'rahu', which displays severe defects in double-strand-break repair and homologous chromosome synapsis during male meiosis, resulting in sterility. rahu is an allele of a transcription unit (Gm14490, renamed Dnmt3c) that was previously mis-annotated as a Dnmt3-family pseudogene. Dnmt3c encodes a cytosine methyltransferase homolog, and Dnmt3crahu mutants harbor a non-synonymous mutation of a conserved residue within one of its cytosine methyltransferase motifs, similar to a mutation in human DNMT3B observed in patients with immunodeficiency, centromeric instability and facial anomalies syndrome. The rahu mutation lies at a potential dimerization interface and near the potential DNA binding interface, suggesting that it compromises protein-protein and/or protein-DNA interactions required for normal DNMT3C function. Dnmt3crahu mutant males fail to establish normal methylation within LINE and LTR retrotransposon sequences in the germline and accumulate higher levels of transposon-derived transcripts and proteins, particularly from distinct L1 and ERVK retrotransposon families. Phylogenetic analysis indicates that Dnmt3c arose during rodent evolution by tandem duplication of Dnmt3b, after the divergence of the Dipodoidea and Muroidea superfamilies. These findings provide insight into the evolutionary dynamics and functional specialization of the transposon suppression machinery critical for mammalian sexual reproduction and epigenetic regulation.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1006964