DNA methylation at retrotransposons protects the germline by preventing NRF1-mediated activation

ABSTRACT: Silencing young retrotransposons by cytosine DNA methylation is essential for spermatogenesis, as failure to methylate their promoters leads to reactivation, meiotic failure, and infertility. How retrotransposons reactivate in the absence of DNA methylation remains poorly understood. We show that upon defective DNA methylation distinct retrotransposon families display unique expression patterns and chromatin landscapes during mouse spermatogenesis. We find that their reactivation in meiotic spermatocytes correlates with the loss of bivalent H3K4me3-H3K27me3 chromatin marks. Through proteomics and chromatin profiling, we identify NRF1 as a DNA methylation-sensitive transcription factor that transactivates unmethylated retrotransposons. Conditional germline knockout of Nrf1 in the absence of DNA methylation rescued the silencing patterns of reactivation of the most mutagenic retrotransposon in mice - Intracisternal A-particle or IAP. Our findings reveal that chromatin modifications together with a DNA methylation-sensitive transcription factor regulate retrotransposons in the absence of DNA methylation in spermatogenesis, highlighting a potential core strategy by which retrotransposons proliferate in the germline after evading DNA methylation-based silencing.

ORGANISM(S): Mus musculus (mouse)

SUBMITTER:  

PROVIDER: S-BSST1977 | biostudies-other |

REPOSITORIES: biostudies-other