Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters. Ablation of the H3K4 methyltransferase gene Mll2 resulted in loss of transcription-independent H3K4 trimethylation but had limited effects on transcription-coupled H3K4 trimethylation or gene expression. Deletion of Dnmt3a and Dnmt3b showed that DNA methylation protects regions from acquiring H3K4me3. Our findings reveal two independent mechanisms of targeting H3K4me3 to genomic elements, with MLL2 recruited to unmethylated CpG-rich regions independently of transcription.

Bioinformatics Group Babraham Institute Cambridge UK

Biotechnology Center TU Dresden Tatzberg Germany

Centre for Trophoblast Research University of Cambridge Cambridge UK

Epigenetics Programme Babraham Institute Cambridge UK

European Research Institute for the Biology of Ageing University of Groningen University Medical Center Groningen Groningen The Netherlands

Institute of Animal Physiology and Genetics ASCR Libechov Czech Republic

Institute of Computational Biology Helmholtz Zentrum München Neuherberg Germany

TUM School of Life Sciences Weihenstephan Technical University of Munich Munich Germany

University of South Bohemia Ceske Budejovice Czech Republic

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