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Nat Struct Mol Biol. 2018 Jan;25(1):73-82. doi: 10.1038/s41594-017-0013-5. Epub 2018 Jan 1.

MLL2 conveys transcription-independent H3K4 trimethylation in oocytes.

Author information

1
Epigenetics Programme, Babraham Institute, Cambridge, UK.
2
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK.
3
Institute of Computational Biology, Helmholtz Zentrum München, Neuherberg, Germany.
4
European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
5
University of South Bohemia, Ceske Budejovice, Czech Republic.
6
Institute of Animal Physiology and Genetics, ASCR, Libechov, Czech Republic.
7
Biotechnology Center TU Dresden, Tatzberg, Germany.
8
Bioinformatics Group, Babraham Institute, Cambridge, UK.
9
Biotechnology Center TU Dresden, Tatzberg, Germany. francis.stewart@tu-dresden.de.
10
TUM School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany.
11
Epigenetics Programme, Babraham Institute, Cambridge, UK. gavin.kelsey@babraham.ac.uk.
12
Centre for Trophoblast Research, University of Cambridge, Cambridge, UK. gavin.kelsey@babraham.ac.uk.

Abstract

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.

PMID:
29323282
DOI:
10.1038/s41594-017-0013-5

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