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Genes Dev. 2015 Dec 1;29(23):2449-62. doi: 10.1101/gad.271353.115. Epub 2015 Nov 19.

Dynamic changes in histone modifications precede de novo DNA methylation in oocytes.

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  • 1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
  • 2Department of Epigenetics and Molecular Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Smithville, Texas 77030, USA;
  • 3Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; Bioinformatics Group, Babraham Institute, Cambridge CB22 3AT, United Kingdom;
  • 4School of Medicine, Yokohama City University, Yokohama 236-0027, Japan;
  • 5Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, United Kingdom; Centre for Trophoblast Research, University of Cambridge CB2 3EG, Cambridge, United Kingdom.


Erasure and subsequent reinstatement of DNA methylation in the germline, especially at imprinted CpG islands (CGIs), is crucial to embryogenesis in mammals. The mechanisms underlying DNA methylation establishment remain poorly understood, but a number of post-translational modifications of histones are implicated in antagonizing or recruiting the de novo DNA methylation complex. In mouse oogenesis, DNA methylation establishment occurs on a largely unmethylated genome and in nondividing cells, making it a highly informative model for examining how histone modifications can shape the DNA methylome. Using a chromatin immunoprecipitation (ChIP) and genome-wide sequencing (ChIP-seq) protocol optimized for low cell numbers and novel techniques for isolating primary and growing oocytes, profiles were generated for histone modifications implicated in promoting or inhibiting DNA methylation. CGIs destined for DNA methylation show reduced protective H3K4 dimethylation (H3K4me2) and trimethylation (H3K4me3) in both primary and growing oocytes, while permissive H3K36me3 increases specifically at these CGIs in growing oocytes. Methylome profiling of oocytes deficient in H3K4 demethylase KDM1A or KDM1B indicated that removal of H3K4 methylation is necessary for proper methylation establishment at CGIs. This work represents the first systematic study performing ChIP-seq in oocytes and shows that histone remodeling in the mammalian oocyte helps direct de novo DNA methylation events.

© 2015 Stewart et al.; Published by Cold Spring Harbor Laboratory Press.


ChIP-seq; DNA methylation; genomic imprinting; histone modifications; oocytes

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