Sex-specific chromatin remodelling safeguards transcription in germ cells Huang, Tien-Chi Wang, Yi-Fang Vázquez-Ferrer, Eric Requena Torres, Cristina Elena Hanna, Courtney W. Kelsey, Gavin Hajkova, Petra MRC London Institute of Medical Sciences (LMS), London, UK. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, London, UK. Stability of the epigenetic landscape underpins maintenance of the cell-type-specific transcriptional profile. As one of the main repressive epigenetic systems, DNA methylation has been shown to be important for long-term gene silencing; its loss leads to ectopic and aberrant transcription in differentiated cells and cancer1. The developing mouse germ line endures global changes in DNA methylation in the absence of widespread transcriptional activation. Here, using an ultra-low-input native chromatin immunoprecipitation approach, we show that following DNA demethylation the gonadal primordial germ cells undergo remodelling of repressive histone modifications, resulting in a sex-specific signature in mice. We further demonstrate that Polycomb has a central role in transcriptional control in the newly hypomethylated germline genome as the genetic loss of Ezh2 leads to aberrant transcriptional activation, retrotransposon derepression and dramatic loss of developing female germ cells. This sex-specific effect of Ezh2 deletion is explained by the distinct landscape of repressive modifications observed in male and female germ cells. Overall, our study provides insight into the dynamic interplay between repressive chromatin modifications in the context of a developmental reprogramming system. 2024-09-27T11:11:21Z 2024-09-27T11:11:21Z 2021-12-08 journal article Published version: Huang, TC., Wang, YF., Vazquez-Ferrer, E. et al. Sex-specific chromatin remodelling safeguards transcription in germ cells. Nature 600, 737–742 (2021). https://doi.org/10.1038/s41586-021-04208-5 https://hdl.handle.net/10481/95211 10.1038/s41586-021-04208-5 eng eu-repo/grantAgreement/EC/FP7/648879 http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Springer Nature