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      Establishment and functions of DNA methylation in the germline

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          Abstract

          Epigenetic modifications established during gametogenesis regulate transcription and other nuclear processes in gametes, but also have influences in the zygote, embryo and postnatal life. This is best understood for DNA methylation which, established at discrete regions of the oocyte and sperm genomes, governs genomic imprinting. In this review, we describe how imprinting has informed our understanding of de novo DNA methylation mechanisms, highlight how recent genome-wide profiling studies have provided unprecedented insights into establishment of the sperm and oocyte methylomes and consider the fate and function of gametic methylation and other epigenetic modifications after fertilization.

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          Conserved Role of Intragenic DNA Methylation in Regulating Alternative Promoters

          While the methylation of DNA in 5′ promoters suppresses gene expression, the role of DNA methylation in gene bodies is unclear 1–5 . In mammals, tissue- and cell type-specific methylation is present in a small percentage of 5′ CpG island (CGI) promoters, while a far greater proportion occurs across gene bodies, coinciding with highly conserved sequences 5–10 . Tissue-specific intragenic methylation might reduce, 3 or, paradoxically, enhance transcription elongation efficiency 1,2,4,5 . Capped analysis of gene expression (CAGE) experiments also indicate that transcription commonly initiates within and between genes 11–15 . To investigate the role of intragenic methylation, we generated a map of DNA methylation from human brain encompassing 24.7 million of the 28 million CpG sites. From the dense, high-resolution coverage of CpG islands, the majority of methylated CpG islands were revealed to be in intragenic and intergenic regions, while less than 3% of CpG islands in 5′ promoters were methylated. The CpG islands in all three locations overlapped with RNA markers of transcription initiation, and unmethylated CpG islands also overlapped significantly with trimethylation of H3K4, a histone modification enriched at promoters 16 . The general and CpG-island-specific patterns of methylation are conserved in mouse tissues. An in-depth investigation of the human SHANK3 locus 17,18 and its mouse homologue demonstrated that this tissue-specific DNA methylation regulates intragenic promoter activity in vitro and in vivo. These methylation-regulated, alternative transcripts are expressed in a tissue and cell type-specific manner, and are expressed differentially within a single cell type from distinct brain regions. These results support a major role for intragenic methylation in regulating cell context-specific alternative promoters in gene bodies.
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            DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA.

            Mammals use DNA methylation for the heritable silencing of retrotransposons and imprinted genes and for the inactivation of the X chromosome in females. The establishment of patterns of DNA methylation during gametogenesis depends in part on DNMT3L, an enzymatically inactive regulatory factor that is related in sequence to the DNA methyltransferases DNMT3A and DNMT3B. The main proteins that interact in vivo with the product of an epitope-tagged allele of the endogenous Dnmt3L gene were identified by mass spectrometry as DNMT3A2, DNMT3B and the four core histones. Peptide interaction assays showed that DNMT3L specifically interacts with the extreme amino terminus of histone H3; this interaction was strongly inhibited by methylation at lysine 4 of histone H3 but was insensitive to modifications at other positions. Crystallographic studies of human DNMT3L showed that the protein has a carboxy-terminal methyltransferase-like domain and an N-terminal cysteine-rich domain. Cocrystallization of DNMT3L with the tail of histone H3 revealed that the tail bound to the cysteine-rich domain of DNMT3L, and substitution of key residues in the binding site eliminated the H3 tail-DNMT3L interaction. These data indicate that DNMT3L recognizes histone H3 tails that are unmethylated at lysine 4 and induces de novo DNA methylation by recruitment or activation of DNMT3A2.
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              Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting.

              Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting, the lethality of Dnmt3a and Dnmt3b knockout mice has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.
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                Author and article information

                Journal
                Epigenomics
                Epigenomics
                EPI
                Epigenomics
                Future Medicine Ltd (London, UK )
                1750-1911
                1750-192X
                October 2016
                23 September 2016
                : 8
                : 10
                : 1399-1413
                Affiliations
                [1 ]Epigenetics Programme, The Babraham Institute, Cambridge, CB22 3AT, UK
                [2 ]Biotech Research & Innovation Centre (BRIC), University of Copenhagen, DK2200 Copenhagen, Denmark
                [3 ]Laboratory of Developmental Biology & Genetics, Department of Molecular Biology, University of South Bohemia, 37005 České Budějovice, Czech Republic
                Author notes
                *Author for correspondence: gavin.kelsey@ 123456babraham.ac.uk

                Authors contributed equally

                Article
                10.2217/epi-2016-0056
                5066131
                27659720
                aa232452-83c1-4e86-8312-59f3af46b377
                © Gavin Kelsey

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 Unported License

                History
                : 11 May 2016
                : 20 July 2016
                Categories
                Review

                dna methylation,embryo,imprinting,oogenesis,spermatogenesis,transgenerational inheritance

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