Transposons are sequences of DNA with the ability to mobilize and jump from one position to another. In the human genome, the number of transposons far surpasses the number of genes. Furthermore, while transposons have been beneficial for the evolution of the human genome, they can also alter genes and cause cancer and genetic diseases.

The danger posed by transposons has led to numerous mechanisms to keep them under control. In particular, a natural biochemical modification of the DNA molecule called “DNA methylation” plays an important role in keeping transposons inactive or silent. However, during the early development of an embryo, the DNA methylation marks are erased throughout the entire genome. This provides an opportunity for transposons to be active, and it is not clear how the genome manages to control transposons in the absence of this essential protective mark.

Walter et al. have now investigated this process by using a cell type that mimics the loss of DNA methylation that occurs during embryonic development – mouse embryonic stem cells grown in the laboratory. The experiments revealed that when DNA methylation is lost progressively, the transposons are reactivated at first but are later put back into a silent mode by alternative mechanisms. These mechanisms compensate for the disappearance of DNA methylation by encouraging the DNA around transposons to become compacted, which prevents the transposons from moving.

Further analysis revealed that the different families of transposons that exist in the mouse genome can be classified into three groups, and in each group different proteins ensure the transposons remain repressed in the absence of DNA methylation. Together these findings reveal that multiple pathways cooperate to protect the genome against the activity of a variety of transposons. Finally, in mammals, DNA methylation is naturally erased both during the formation of sperm and egg cells and in the early embryo. As such, it will be important to verify whether the mechanisms discovered in the laboratory-grown cells also tame transposons during these critical developmental periods.

Millions of transposable elements reside in mammalian genomes, far surpassing in number the approximately 25000 protein-coding genes (Lander et al., 2001). Most of these elements are retrotransposons, which utilize an RNA intermediate to duplicate and mobilize. Through their activity or their mere presence, transposons can be both beneficial for the evolution of the host genome and deleterious for its integrity. They can modify gene functions through insertional mutagenesis, influence gene transcriptional outputs by acting as promoters or enhancers or induce chromosomal rearrangements through non-allelic recombination (Goodier and Kazazian, 2008). Accordingly, erratic transposon-related events have been linked to congenital diseases, cancer and infertility (Kaer and Speek, 2013).

Successive waves of transposon expansion and decline have shaped mammalian genomes over evolution, leading to a current occupancy rate of approximately half of the genomic space. Reflecting their various evolutionary origin and multiplication success, resident elements are greatly diverse in structures, numbers and functional properties, which define discrete families of transposons. Long Terminal Repeat (LTR) sequences characterize endogenous retroviruses (ERVs, 12% of the mouse genome), which can be further subdivided into three families (ERV1, ERVK and ERVL), according to the infectious retroviruses they derive from (Stocking and Kozak, 2008). Non-LTR elements comprise Long and Short INterspersed Elements (LINEs and SINEs, 20% and 8% of the genome, respectively), and also consist of specific sub-families (Babushok et al., 2007). The majority of transposons have accumulated nullifying mutations and truncations, but around 1–2% of LINEs and ERVs have intact sequences that embed the protein coding information necessary for their mobilization. Notably, ERVK elements show the greatest level of activity, which causes at least 10% of spontaneous mutations in laboratory mice (Maksakova et al., 2006).

To minimize their impact on genome fitness, multiple layers of control antagonize transposons at different steps of their life cycle (Zamudio and Bourc’his, 2010). Notably, restraining mechanisms can differ between cell types. In somatic cells and in the male differentiating germline, DNA methylation is the main transcriptional suppressor of LTR and non-LTR transposons. In these contexts, transposable elements are densely methylated (Rollins et al., 2006; Smith et al., 2012) and DNA hypomethylation leads to their de-repression (Bourc’his and Bestor, 2004; Walsh et al., 1998). In contrast, the early germline and the early embryo manage to globally control their transposon burden without DNA methylation. These cells naturally undergo genome-wide loss of DNA methylation, likely as part of the acquisition of a pluripotent, flexible state (Seisenberger et al., 2013). Moreover, genetic studies have demonstrated that mouse embryonic stem (ES) cells can use DNA methylation-independent mechanisms to silence transposons: knocking-out the three active DNA methyltransferases (Dnmt-tKO) does not yield significant de-repression of transposons, except Intracisternal A Particle (IAP) elements (Karimi et al., 2011b; Matsui et al., 2010)

In fact, transposon control in ES cells seems to rely primarily on post-translational histone methylation, notably at lysine 9 of histone H3 (H3K9). H3K9 dimethylation (H3K9me2), which is deposited by the EHMT2/G9a and EHMT1/GLP lysine methyltransferases, directly and specifically represses class L ERVs (Maksakova et al., 2013). H3K9 trimethylation (H3K9me3) can be catalyzed by the SETDB1 (also known as ESET) or the SUV39H enzymes. The SUV39H system targets H3K9me3 at evolutionary young LTR and non-LTR transposons, but Suv39h mutant ES cells principally up-regulate LINE1 elements (Bulut-Karslioglu et al., 2014). In parallel, SETDB1, together with its associated co-repressor, the Krüppel-associated box domain (KRAB)-Associated Protein 1 (TRIM28, also known as KAP1), mainly control H3K9me3-dependent suppression of ERVK transposons- a family to which IAP elements belong (Karimi et al., 2011b; Matsui et al., 2010; Rowe et al., 2010). TRIM28 is recruited to specific genomic sites via direct interactions with KRAB-zinc finger proteins (Friedman et al., 1996), which are a large family of DNA binding factors that co-evolved with ERVs (Emerson and Thomas, 2009). Therefore, different H3K9 methylation-based mechanisms are utilized to silence different transposons families in ES cells. In contrast, the repressive spectrum of polycomb-mediated H3 lysine 27 trimethylation (H3K27me3) is limited: only Murine Leukemia Virus (MuLV) elements are reactivated upon H3K27me3 deficiency (Leeb et al., 2010).

However, the prevailing view that H3K9 methylation acts as the main transposon controller in ES cells may be biased by two confounding factors. First, conclusions are based on analyses of chromatin modifier mutants, which still harbor high DNA methylation levels. Second, proper transposon repression in Dnmt-tKO ES cells may reflect a long-term adaptation to a DNA methylation-free state rather than a lack of significant role of DNA methylation per se. In fact, how the ES cell genome transitions from a DNA methylation-dependent to -independent mode of transposon control has never been investigated.

To study the dynamics of transposon regulation upon DNA methylation loss, we modulated the ES cell methylome by using interconvertible culture systems, which do not modify pluripotency potential. ES cells grown in standard serum-based conditions have heavily methylated genomes (~75% of CpG methylation)(Stadler et al., 2011), which is linked to the expression of de novo DNA methyltransferases. ES cells grown in presence of two small kinase inhibitors (2i) down-regulate these enzymes, and have reduced DNA methylation levels (Leitch et al., 2013; Ying et al., 2008). Upon transfer from serum to 2i medium, demethylation occurs with a slow kinetics: several weeks are required to reach 20–30% of CpG methylation. Notably, imprinted genes, major satellite repeats and IAP elements maintain persistent DNA methylation after 2i adaptation (Ficz et al., 2013; Habibi et al., 2013). Addition of vitamin C (vitC) can also lower the ES cell methylome. This compound promotes active demethylation by stimulating the TET (Ten Eleven Translocation) enzymes, which oxidize 5-methylcytosines to 5-hydroxymethylcytosines that are potential intermediates towards unmethylated cytosines (Blaschke et al., 2013).

Here, by switching ES cells directly from a serum-based to a 2i+vitC medium, we were able to induce rapid and extensive demethylation genome-wide, mimicking a situation occurring in the early embryo. By combining DNA methylation, chromatin and transcriptional profiling of transposons along with genetic analyses, we found that DNA methylation represses multiple families of transposons in ES cells, but an epigenetic switch towards histone-based control is progressively implemented as DNA methylation disappears. Importantly, we reveal for the first time the specific and overlapping roles of H3K9 and H3K27 trimethylation in controlling distinct transposon families upon DNA demethylation. These findings have important implications for understanding the molecular underpinning of transposon control in the pluripotent cells of the early mammalian embryo.

Our study provides unprecedented insight into the dynamic adaptation of the pluripotent genome to a loss of DNA methylation-based control of transposons. This was achieved through detailed kinetic assessment of transcription and chromatin states during conversion of WT ES cells from serum to 2i+vitC media, as a way to reproduce the DNA methylation erasure that occurs during embryogenesis. Despite their heterogeneous origins and structures, we found that various transposon families residing in the mouse genome adopted a common regulatory fate: after an initial transcriptional burst, repression was re-established in a DNA methylation-independent manner. Distinct combinations of H3K9me2/3 and H3K27me3 were observed among transposon families, defining three functional categories of chromatin-based responses to DNA methylation loss: joint H3K9me3 and H3K27m3 (A), H3K9me3-exclusive (B), and H3K27me3-exclusive (C) (Figure 8). Importantly, Dnmt-tKO cells, which have endured long-term adaptation to a DNA methylation-free state, displayed similar transposon-specific chromatin patterns when grown in serum, which excludes a medium-related effect. In conclusion, our work revises the previous assumption that DNA methylation is dispensable for transposon silencing in ES cells; rather, we reveal here that various histone-based repression strategies are implemented upon DNA methylation loss, thereby safeguarding pluripotent cells against a multitude of heterogeneous transposon entities.

Figure 8

Download asset Open asset

Upon 2i+vitC-mediated DNA methylation loss, the repertoire of repressive histone marks is profoundly remodeled (Figure 8A): H3K9me2 enrichment decreases, while H3K27me3 is enhanced and H3K9me3 levels are globally constant. Interestingly, repressive chromatin reorganization has also been cytologically observed in primordial germ cells (PGCs) undergoing genome-wide demethylation (Hajkova et al., 2008; Seki et al., 2007). Moreover, the relocalization of H3K27me3 at transposons and its co-occurrence with H3K9me3 was also reported in hypomethylated PGCs (Liu et al., 2014). Our cellular system could therefore represent an adequate model to study in vivo events of chromatin reprogramming occurring at transposons upon DNA methylation loss.

The persistence of H3K9me3 upon loss of DNA methylation highlights that DNA methylation does not exert significant control over H3K9me3-targeting of transposons in ES cells. Interestingly, we consistently observed that regions of persistent DNA methylation (RMRs) coincide with high H3K9me3 enrichment on transposon sequences in fully 2i+vitC-converted cells, e.g. on the 5’ end of LINE1 elements and throughout the length of ERVK elements. This supports previous evidence that H3K9me3 can confer protection against DNA demethylation (Leung et al., 2014). Inversely, the rapid disappearance of H3K9me2 upon serum to 2i+vitC conversion could reflect a direct role of DNA methylation in the maintenance of these marks. Accordingly, H3K9me2 reduction was also observed in DNA methylation-free Dnmt-tKO ES cells grown in serum (data not shown). Coupled losses of DNA methylation and H3K9me2 have also been previously reported in vivo, during normal primordial germ cell development (Hajkova et al., 2008; Seki et al., 2005) and in DNA methylation-deficient spermatocytes (Zamudio et al., 2015). A mechanism of H3K9me2 methyltransferase recruitment via DNA methylation has been resolved in plants (Du et al., 2015); the evolution of an analogous mechanism in mammals should be explored.

Of particular importance to this study is our observation of an epigenetic switch occurring between DNA methylation- and H3K27me3-based control. H3K27me3 is barely detectable at transposons in DNA hypermethylated WT ES cells grown in serum; in contrast, transposons accumulate H3K27me3 in both 2i+vitC-converted cells and in serum-grown Dnmt-tKO cells. This is in line with the prevailing notion that DNA methylation and H3K27me3 are mutually exclusive genome-wide and that DNA methylation antagonizes H3K27me3 deposition (Brinkman et al., 2012; Jermann et al., 2014; Tanay et al., 2007). Saliently, this raises the question as to how transposons acquire H3K27me3 upon DNA methylation loss. In mammalian genomes, polycomb is typically targeted to unmethylated GC-rich gene promoters (Jermann et al., 2014; Mendenhall et al., 2010). Notably, transposon sequences have a GC content superior to the genome average (Figure 5—figure supplement 2B): this signature could be sufficient to attract polycomb-mediated H3K27me3 deposition in the absence of DNA methylation. Intermediate methyl-sensitive DNA binding proteins may be involved: the BEND3 protein was recently identified as a sensor of DNA methylation states at pericentromeric repeats, recruiting polycomb-dependent H3K27me3 marks in Dnmt-tKO ES cells (Saksouk et al., 2014). Interestingly, we also observed H3K27me3 relocalization towards pericentromeric repeats in hypomethylated 2i+vitC ES cells. Similarly, the H3K36 demethylase KDM2B, which targets unmethylated CpG-rich sequences, was shown to recruit PRC1, potentially leading to H3K27me3 deposition through PRC2 recruitment (Blackledge et al., 2014; Farcas et al., 2012). Comparable mechanisms might be at play for the recruitment of H3K27me3 at hypomethylated transposons, involving BEND3, KDM2B and/or other methyl-sensitive DNA binding proteins.

Thus, based on previous observations, we posit that H3K27me3 invades the transposon space left unmarked by DNA methylation upon 2i+vitC conversion. Moreover, we provide evidence that the three possible chromatin configurations that the different transposon families adopt are further determined by H3K9me3 occupancy (Figure 8B). Mutual exclusion between H3K9me3 and H3K27me3 marks has been previously documented at gene promoters and pericentromeric repeats (Mikkelsen et al., 2007; Peters et al., 2003), but not at transposons. We found that category B transposons, which constantly maintain H3K9me3 marks throughout their entire length, do not acquire H3K27me3-based chromatin even though they lose DNA methylation. In contrast, category C transposons, exemplified by MERVL elements, become strongly enriched for H3K27me3 as H3K9me2/3 depletes during medium conversion. Finally, category A elements provide a striking illustration of the physical segregation of H3K9me3 and H3K27me3: as H3K9me3 constitutively marks the 5’ end of this transposon category, only their 3’ end is accessible to H3K27me3 deposition upon DNA methylation loss. The presence of H3K27me3 at the 3’ end of transcription units has not been described before and its functional significance was unknown. Our transcriptome analysis of 2i+vitC-converted Eed-KO cells reveals that 3’ end enrichment of H3K27me3 does not confer transcriptional repression of transposons of the A category: it may rather represent a passive response to the lack of DNA methylation and H3K9me3 at this position.

The main message conveyed by our work is that compensatory histone-based mechanisms ensure transposon silencing when DNA methylation-based control is alleviated in ES cells. We cannot rule out that other mechanisms-such as small RNA-based post-transcriptional repression-could also participate to transposon control. Importantly, genetic analyses globally confirmed the functionality of the chromatin patterns that we identified. In particular, H3K27me3-dependency was very well illustrated by the failure to repress several transposon families – in particular MERVL and LINE1– in Eed-KO ES cells undergoing medium-based DNA methylation loss. However, the transposon category B (IAPEz), which remains enriched for H3K9me3 throughout media conversion, gave complex, disparate phenotypes in the mutants of the different H3K9me3 pathways. While these elements failed to be repressed in Setdb1 and Trim28-deficient ES cells, the complete suppression of IAPEz reactivation in Suv39-dko cells was unexpected. We suspect that alternative repressive processes likely obscure IAPEz transcriptional responses to DNA methylation loss in this mutant. This is akin to Dnmt-tKO cells, which also exhibit global transposon repression. Thus, our analyses highlight the possible unexplained phenotypes of mutant cells that have adapted to long-term chromatin-based deficiencies.

Finally, one important point to raise is that the epigenetic switch from a DNA methylation-dependent to -independent mode of transposon silencing is not perfectly synchronized: ES cells experience an acute burst of transposon expression at D6 of medium conversion. At this time point, we showed that DNA methylation has been mostly erased but H3K27me3 patterns have not been established yet. Interestingly, the stability of H3K9me3 marks at category A and B transposons is not sufficient to ensure their continuous silencing upon conversion. This may imply that H3K9me3 readers are transiently deficient in this system. The lag between DNA methylation loss and subsequent implementation of histone-based repression could create an opportunistic window for transposon reactivation, provided that adequate transcription factors are available. Several studies have previously pointed out that transposons are enriched in pluripotency transcription factor binding motifs (Kunarso et al., 2010; Wang et al., 2014), in particular for NANOG and OCT4, and that upregulation of these transcription factors was sufficient to promote transposon expression (Grow et al., 2015).

We propose that the simultaneous disappearance of DNA methylation marks and increased availability of pluripotency activators create favorable conditions to transposon expression at D6 of serum to 2i+vitC conversion (Figure 8B). After a brief silencing release, functional repressive chromatin is recovered, in an H3K9me3 and/or H3K27me3-dependent manner. Notably, we repeatedly observed a peak of massive cell death of H3K27me3-deficient Eed-KO ES cells between D6 and D10 of medium conversion, when DNA methylation has mostly disappeared. This phenotype was even exacerbated in Suv39h-Eed-tKO ES cells, which did not survive after a week of medium conversion. These observations support the critical role for H3K27me3 in supplementing DNA methylation-based control in ES cells.

1. 1. Walter M
   2. Teissandier A
   3. Pérez Palacios R
   4. Bourc'his D

   (2015) An epigenetic switch ensures transposon repression upon acute loss of DNA methylation in ES cells

   Publicly available at the NCBI Gene Expression Omnibus (Accession no: GSE71593).

   http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71593

1. 1. Seisenberger S
   2. Andrews S
   3. Krueger F
   4. Arand J
   5. Walter J
   6. Santos F
   7. Popp C
   8. Thienpont B
   9. Dean W
   10. Reik W

   (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells

   Publicly available at the EBI European Nucleotide Archive (Accession no: ERP001953).

   http://www.ebi.ac.uk/ena/data/view/ERP001953
2. 1. Marks H
   2. Habibi E
   3. Brinkman AB
   4. Arand J
   5. Kroeze LI
   6. Kerstens HH
   7. Matarese F
   8. Lepikhov K
   9. Gut M
   10. Brun-Heath I
   11. Hubner NC
   12. Benedetti R
   13. Altucci L
   14. Jansen JH
   15. Walter J
   16. Gut IG
   17. Stunnenberg HG

   (2013) Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells

   Publicly available at the NCBI Gene Expression Omnibus (Accession no: GSE41923).

   http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE41923
3. 1. Brinkman AB
   2. Gu H
   3. Bartels SJ
   4. Zhang Y
   5. Matarese F
   6. Simmer F
   7. Marks H
   8. Bock C
   9. Gnirke A
   10. Meissner A
   11. Stunnenberg HG

   (2012) Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk

   Publicly available at the NCBI Gene Expression Omnibus (Accession no: GSE28254).

   http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE28254

1. 1. Akalin A
   2. Kormaksson M
   3. Li S
   4. Garrett-Bakelman FE
   5. Figueroa ME
   6. Melnick A
   7. Mason CE

   (2012) MethylKit: a comprehensive r package for the analysis of genome-wide DNA methylation profiles

   Genome Biology 13:R87.

   https://doi.org/10.1186/gb-2012-13-10-r87

   • Google Scholar
2. 1. Anders S
   2. Pyl PT
   3. Huber W

   (2015) HTSeq--a python framework to work with high-throughput sequencing data

   Bioinformatics 31:166–169.

   https://doi.org/10.1093/bioinformatics/btu638

   • Google Scholar
3. 1. Babushok DV
   2. Kazazian HH

   (2007) Progress in understanding the biology of the human mutagen LINE-1

   Human Mutation 28:527–539.

   https://doi.org/10.1002/humu.20486

   • Google Scholar
4. 1. Bailly-Bechet M
   2. Haudry A
   3. Lerat E

   (2014) “one code to find them all”: a perl tool to conveniently parse RepeatMasker output files

   Mobile DNA 5:13.

   https://doi.org/10.1186/1759-8753-5-13

   • Google Scholar
5. 1. Blackledge NP
   2. Farcas AM
   3. Kondo T
   4. King HW
   5. McGouran JF
   6. Hanssen LL
   7. Ito S
   8. Cooper S
   9. Kondo K
   10. Koseki Y
   11. Ishikura T
   12. Long HK
   13. Sheahan TW
   14. Brockdorff N
   15. Kessler BM
   16. Koseki H
   17. Klose RJ

   (2014) Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation

   Cell 157:1445–1459.

   https://doi.org/10.1016/j.cell.2014.05.004

   • Google Scholar
6. 1. Blaschke K
   2. Ebata KT
   3. Karimi MM
   4. Zepeda-Martínez JA
   5. Goyal P
   6. Mahapatra S
   7. Tam A
   8. Laird DJ
   9. Hirst M
   10. Rao A
   11. Lorincz MC
   12. Ramalho-Santos M

   (2013) Vitamin c induces tet-dependent DNA demethylation and a blastocyst-like state in ES cells

   Nature 500:222–226.

   https://doi.org/10.1038/nature12362

   • Google Scholar
7. 1. Bourc'his D
   2. Bestor TH

   (2004) Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L

   Nature 431:96–99.

   https://doi.org/10.1038/nature02886

   • Google Scholar
8. 1. Brinkman AB
   2. Gu H
   3. Bartels SJ
   4. Zhang Y
   5. Matarese F
   6. Simmer F
   7. Marks H
   8. Bock C
   9. Gnirke A
   10. Meissner A
   11. Stunnenberg HG

   (2012) Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk

   Genome Research 22:1128–1138.

   https://doi.org/10.1101/gr.133728.111

   • Google Scholar
9. 1. Bulut-Karslioglu A
   2. De La Rosa-Velázquez IA
   3. Ramirez F
   4. Barenboim M
   5. Onishi-Seebacher M
   6. Arand J
   7. Galán C
   8. Winter GE
   9. Engist B
   10. Gerle B
   11. O'Sullivan RJ
   12. Martens JH
   13. Walter J
   14. Manke T
   15. Lachner M
   16. Jenuwein T

   (2014) Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells

   Molecular Cell 55:277–290.

   https://doi.org/10.1016/j.molcel.2014.05.029

   • Google Scholar
10. 1. Cong L
    2. Ran FA
    3. Cox D
    4. Lin S
    5. Barretto R
    6. Habib N
    7. Hsu PD
    8. Wu X
    9. Jiang W
    10. Marraffini LA
    11. Zhang F

    (2013) Multiplex genome engineering using CRISPR/Cas systems

    Science (New York, N.Y.) 339:819–823.

    https://doi.org/10.1126/science.1231143

    • Google Scholar
11. 1. Dodge JE
    2. Kang YK
    3. Beppu H
    4. Lei H
    5. Li E

    (2004)

    Histone H3-K9 methyltransferase ESET is essential for early development

    Molecular and Cellular Biology 24:2478–2486.

    • Google Scholar
12. 1. Du J
    2. Johnson LM
    3. Jacobsen SE
    4. Patel DJ

    (2015) DNA methylation pathways and their crosstalk with histone methylation

    Nature Reviews. Molecular Cell Biology 16:519–532.

    https://doi.org/10.1038/nrm4043

    • Google Scholar
13. 1. Emerson RO
    2. Thomas JH

    (2009) Adaptive evolution in zinc finger transcription factors

    PLoS Genetics 5:e1000325.

    https://doi.org/10.1371/journal.pgen.1000325

    • Google Scholar
14. 1. Farcas AM
    2. Blackledge NP
    3. Sudbery I
    4. Long HK
    5. McGouran JF
    6. Rose NR
    7. Lee S
    8. Sims D
    9. Cerase A
    10. Sheahan TW
    11. Koseki H
    12. Brockdorff N
    13. Ponting CP
    14. Kessler BM
    15. Klose RJ

    (2012) KDM2B links the polycomb repressive complex 1 (pRC1) to recognition of CpG islands

    eLife 1:e00205.

    https://doi.org/10.7554/eLife.00205

    • Google Scholar
15. 1. Ficz G
    2. Hore TA
    3. Santos F
    4. Lee HJ
    5. Dean W
    6. Arand J
    7. Krueger F
    8. Oxley D
    9. Paul YL
    10. Walter J
    11. Cook SJ
    12. Andrews S
    13. Branco MR
    14. Reik W

    (2013) FGF signaling inhibition in ESCs drives rapid genome-wide demethylation to the epigenetic ground state of pluripotency

    Cell Stem Cell 13:351–359.

    https://doi.org/10.1016/j.stem.2013.06.004

    • Google Scholar
16. 1. Friedman JR
    2. Fredericks WJ
    3. Jensen DE
    4. Speicher DW
    5. Huang XP
    6. Neilson EG
    7. Rauscher FJ

    (1996) KAP-1, a novel corepressor for the highly conserved KRAB repression domain

    Genes & Development 10:2067–2078.

    https://doi.org/10.1101/gad.10.16.2067

    • Google Scholar
17. 1. Fritsch L
    2. Robin P
    3. Mathieu JR
    4. Souidi M
    5. Hinaux H
    6. Rougeulle C
    7. Harel-Bellan A
    8. Ameyar-Zazoua M
    9. Ait-Si-Ali S

    (2010) A subset of the histone H3 lysine 9 methyltransferases Suv39h1, G9a, GLP, and SETDB1 participate in a multimeric complex

    Molecular Cell 37:46–56.

    https://doi.org/10.1016/j.molcel.2009.12.017

    • Google Scholar
18. 1. Goodier JL
    2. Kazazian HH

    (2008) Retrotransposons revisited: the restraint and rehabilitation of parasites

    Cell 135:23–35.

    https://doi.org/10.1016/j.cell.2008.09.022

    • Google Scholar
19. 1. Grow EJ
    2. Flynn RA
    3. Chavez SL
    4. Bayless NL
    5. Wossidlo M
    6. Wesche DJ
    7. Martin L
    8. Ware CB
    9. Blish CA
    10. Chang HY
    11. Pera RA
    12. Wysocka J

    (2015) Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells

    Nature 522:.

    https://doi.org/10.1038/nature14308

    • Google Scholar
20. 1. Habibi E
    2. Brinkman AB
    3. Arand J
    4. Kroeze LI
    5. Kerstens HH
    6. Matarese F
    7. Lepikhov K
    8. Gut M
    9. Brun-Heath I
    10. Hubner NC
    11. Benedetti R
    12. Altucci L
    13. Jansen JH
    14. Walter J
    15. Gut IG
    16. Marks H
    17. Stunnenberg HG

    (2013) Whole-genome bisulfite sequencing of two distinct interconvertible DNA methylomes of mouse embryonic stem cells

    Cell Stem Cell 13:360–369.

    https://doi.org/10.1016/j.stem.2013.06.002

    • Google Scholar
21. 1. Hajkova P
    2. Ancelin K
    3. Waldmann T
    4. Lacoste N
    5. Lange UC
    6. Cesari F
    7. Lee C
    8. Almouzni G
    9. Schneider R
    10. Surani MA

    (2008) Chromatin dynamics during epigenetic reprogramming in the mouse germ line

    Nature 452:877–881.

    https://doi.org/10.1038/nature06714

    • Google Scholar
22. 1. Heinz S
    2. Benner C
    3. Spann N
    4. Bertolino E
    5. Lin YC
    6. Laslo P
    7. Cheng JX
    8. Murre C
    9. Singh H
    10. Glass CK

    (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and b cell identities

    Molecular Cell 38:576–589.

    https://doi.org/10.1016/j.molcel.2010.05.004

    • Google Scholar
23. 1. Hsu PD
    2. Scott DA
    3. Weinstein JA
    4. Ran FA
    5. Konermann S
    6. Agarwala V
    7. Li Y
    8. Fine EJ
    9. Wu X
    10. Shalem O
    11. Cradick TJ
    12. Marraffini LA
    13. Bao G
    14. Zhang F

    (2013) DNA targeting specificity of RNA-guided Cas9 nucleases

    Nature Biotechnology 31:827–832.

    https://doi.org/10.1038/nbt.2647

    • Google Scholar
24. 1. Illingworth RS
    2. Gruenewald-Schneider U
    3. Webb S
    4. Kerr AR
    5. James KD
    6. Turner DJ
    7. Smith C
    8. Harrison DJ
    9. Andrews R
    10. Bird AP

    (2010) Orphan CpG islands identify numerous conserved promoters in the mammalian genome

    PLoS Genetics 6:e1001134.

    https://doi.org/10.1371/journal.pgen.1001134

    • Google Scholar
25. 1. Jermann P
    2. Hoerner L
    3. Burger L
    4. Schübeler D

    (2014) Short sequences can efficiently recruit histone H3 lysine 27 trimethylation in the absence of enhancer activity and DNA methylation

    Proceedings of the National Academy of Sciences of the United States of America 111:E3415.

    https://doi.org/10.1073/pnas.1400672111

    • Google Scholar
26. 1. Kaer K
    2. Speek M

    (2013) Retroelements in human disease

    Gene 518:231–241.

    https://doi.org/10.1016/j.gene.2013.01.008

    • Google Scholar
27. Book

    1. Karimi M
    2. Luttropp K
    3. Ekström TJ
    4. Mikeska T
    5. Felsberg J
    6. Hewitt C. a
    7. Dobrovic A

    (2011a)

    Epigenetics Protocols, Volume 791

    New York, NY: Springer.

    • Google Scholar
28. 1. Karimi MM
    2. Goyal P
    3. Maksakova IA
    4. Bilenky M
    5. Leung D
    6. Tang JX
    7. Shinkai Y
    8. Mager DL
    9. Jones S
    10. Hirst M
    11. Lorincz MC

    (2011b) DNA methylation and SETDB1/H3K9me3 regulate predominantly distinct sets of genes, retroelements, and chimeric transcripts in mESCs

    Cell Stem Cell 8:676–687.

    https://doi.org/10.1016/j.stem.2011.04.004

    • Google Scholar
29. 1. Kim D
    2. Pertea G
    3. Trapnell C
    4. Pimentel H
    5. Kelley R
    6. Salzberg SL

    (2013) TopHat2: accurate alignment of transcriptomes in the presence of insertions, deletions and gene fusions

    Genome Biology 14:R36.

    https://doi.org/10.1186/gb-2013-14-4-r36

    • Google Scholar
30. 1. Krueger F
    2. Andrews SR

    (2011) Bismark: a flexible aligner and methylation caller for bisulfite-seq applications

    Bioinformatics 27:1571–1572.

    https://doi.org/10.1093/bioinformatics/btr167

    • Google Scholar
31. 1. Kunarso G
    2. Chia NY
    3. Jeyakani J
    4. Hwang C
    5. Lu X
    6. Chan YS
    7. Ng HH
    8. Bourque G

    (2010) Transposable elements have rewired the core regulatory network of human embryonic stem cells

    Nature Genetics 42:631–634.

    https://doi.org/10.1038/ng.600

    • Google Scholar
32. 1. Lander ES
    2. Linton LM
    3. Birren B
    4. Nusbaum C
    5. Zody MC
    6. Baldwin J
    7. Devon K
    8. Dewar K
    9. Doyle M
    10. FitzHugh W
    11. Funke R
    12. Gage D
    13. Harris K
    14. Heaford A
    15. Howland J
    16. Kann L
    17. Lehoczky J
    18. LeVine R
    19. McEwan P
    20. McKernan K
    21. Meldrim J
    22. Mesirov JP
    23. Miranda C
    24. Morris W
    25. Naylor J
    26. Raymond C
    27. Rosetti M
    28. Santos R
    29. Sheridan A
    30. Sougnez C
    31. Stange-Thomann Y
    32. Stojanovic N
    33. Subramanian A
    34. Wyman D
    35. Rogers J
    36. Sulston J
    37. Ainscough R
    38. Beck S
    39. Bentley D
    40. Burton J
    41. Clee C
    42. Carter N
    43. Coulson A
    44. Deadman R
    45. Deloukas P
    46. Dunham A
    47. Dunham I
    48. Durbin R
    49. French L
    50. Grafham D
    51. Gregory S
    52. Hubbard T
    53. Humphray S
    54. Hunt A
    55. Jones M
    56. Lloyd C
    57. McMurray A
    58. Matthews L
    59. Mercer S
    60. Milne S
    61. Mullikin JC
    62. Mungall A
    63. Plumb R
    64. Ross M
    65. Shownkeen R
    66. Sims S
    67. Waterston RH
    68. Wilson RK
    69. Hillier LW
    70. McPherson JD
    71. Marra MA
    72. Mardis ER
    73. Fulton LA
    74. Chinwalla AT
    75. Pepin KH
    76. Gish WR
    77. Chissoe SL
    78. Wendl MC
    79. Delehaunty KD
    80. Miner TL
    81. Delehaunty A
    82. Kramer JB
    83. Cook LL
    84. Fulton RS
    85. Johnson DL
    86. Minx PJ
    87. Clifton SW
    88. Hawkins T
    89. Branscomb E
    90. Predki P
    91. Richardson P
    92. Wenning S
    93. Slezak T
    94. Doggett N
    95. Cheng JF
    96. Olsen A
    97. Lucas S
    98. Elkin C
    99. Uberbacher E
    100. Frazier M
    101. Gibbs RA
    102. Muzny DM
    103. Scherer SE
    104. Bouck JB
    105. Sodergren EJ
    106. Worley KC
    107. Rives CM
    108. Gorrell JH
    109. Metzker ML
    110. Naylor SL
    111. Kucherlapati RS
    112. Nelson DL
    113. Weinstock GM
    114. Sakaki Y
    115. Fujiyama A
    116. Hattori M
    117. Yada T
    118. Toyoda A
    119. Itoh T
    120. Kawagoe C
    121. Watanabe H
    122. Totoki Y
    123. Taylor T
    124. Weissenbach J
    125. Heilig R
    126. Saurin W
    127. Artiguenave F
    128. Brottier P
    129. Bruls T
    130. Pelletier E
    131. Robert C
    132. Wincker P
    133. Smith DR
    134. Doucette-Stamm L
    135. Rubenfield M
    136. Weinstock K
    137. Lee HM
    138. Dubois J
    139. Rosenthal A
    140. Platzer M
    141. Nyakatura G
    142. Taudien S
    143. Rump A
    144. Yang H
    145. Yu J
    146. Wang J
    147. Huang G
    148. Gu J
    149. Hood L
    150. Rowen L
    151. Madan A
    152. Qin S
    153. Davis RW
    154. Federspiel NA
    155. Abola AP
    156. Proctor MJ
    157. Myers RM
    158. Schmutz J
    159. Dickson M
    160. Grimwood J
    161. Cox DR
    162. Olson MV
    163. Kaul R
    164. Raymond C
    165. Shimizu N
    166. Kawasaki K
    167. Minoshima S
    168. Evans GA
    169. Athanasiou M
    170. Schultz R
    171. Roe BA
    172. Chen F
    173. Pan H
    174. Ramser J
    175. Lehrach H
    176. Reinhardt R
    177. McCombie WR
    178. de la Bastide M
    179. Dedhia N
    180. Blöcker H
    181. Hornischer K
    182. Nordsiek G
    183. Agarwala R
    184. Aravind L
    185. Bailey JA
    186. Bateman A
    187. Batzoglou S
    188. Birney E
    189. Bork P
    190. Brown DG
    191. Burge CB
    192. Cerutti L
    193. Chen HC
    194. Church D
    195. Clamp M
    196. Copley RR
    197. Doerks T
    198. Eddy SR
    199. Eichler EE
    200. Furey TS
    201. Galagan J
    202. Gilbert JG
    203. Harmon C
    204. Hayashizaki Y
    205. Haussler D
    206. Hermjakob H
    207. Hokamp K
    208. Jang W
    209. Johnson LS
    210. Jones TA
    211. Kasif S
    212. Kaspryzk A
    213. Kennedy S
    214. Kent WJ
    215. Kitts P
    216. Koonin EV
    217. Korf I
    218. Kulp D
    219. Lancet D
    220. Lowe TM
    221. McLysaght A
    222. Mikkelsen T
    223. Moran JV
    224. Mulder N
    225. Pollara VJ
    226. Ponting CP
    227. Schuler G
    228. Schultz J
    229. Slater G
    230. Smit AF
    231. Stupka E
    232. Szustakowki J
    233. Thierry-Mieg D
    234. Thierry-Mieg J
    235. Wagner L
    236. Wallis J
    237. Wheeler R
    238. Williams A
    239. Wolf YI
    240. Wolfe KH
    241. Yang SP
    242. Yeh RF
    243. Collins F
    244. Guyer MS
    245. Peterson J
    246. Felsenfeld A
    247. Wetterstrand KA
    248. Patrinos A
    249. Morgan MJ
    250. de Jong P
    251. Catanese JJ
    252. Osoegawa K
    253. Shizuya H
    254. Choi S
    255. Chen YJ
    256. Szustakowki J
    257. International Human Genome Sequencing Consortium

    (2001) Initial sequencing and analysis of the human genome

    Nature 409:860–921.

    https://doi.org/10.1038/35057062

    • Google Scholar
33. 1. Langmead B
    2. Salzberg SL

    (2012) Fast gapped-read alignment with bowtie 2

    Nature Methods 9:357–359.

    https://doi.org/10.1038/nmeth.1923

    • Google Scholar
34. 1. Law CW
    2. Chen Y
    3. Shi W
    4. Smyth GK

    (2014) Voom: precision weights unlock linear model analysis tools for RNA-seq read counts

    Genome Biology 15:R29.

    https://doi.org/10.1186/gb-2014-15-2-r29

    • Google Scholar
35. 1. Leeb M
    2. Pasini D
    3. Novatchkova M
    4. Jaritz M
    5. Helin K
    6. Wutz A

    (2010) Polycomb complexes act redundantly to repress genomic repeats and genes

    Genes & Development 24:265–276.

    https://doi.org/10.1101/gad.544410

    • Google Scholar
36. 1. Leitch HG
    2. McEwen KR
    3. Turp A
    4. Encheva V
    5. Carroll T
    6. Grabole N
    7. Mansfield W
    8. Nashun B
    9. Knezovich JG
    10. Smith A
    11. Surani MA
    12. Hajkova P

    (2013) Naive pluripotency is associated with global DNA hypomethylation

    Nature Structural & Molecular Biology 20:311–316.

    https://doi.org/10.1038/nsmb.2510

    • Google Scholar
37. 1. Leung D
    2. Du T
    3. Wagner U
    4. Xie W
    5. Lee AY
    6. Goyal P
    7. Li Y
    8. Szulwach KE
    9. Jin P
    10. Lorincz MC
    11. Ren B

    (2014) Regulation of DNA methylation turnover at LTR retrotransposons and imprinted loci by the histone methyltransferase Setdb1

    Proceedings of the National Academy of Sciences of the United States of America 111:6690–6695.

    https://doi.org/10.1073/pnas.1322273111

    • Google Scholar
38. 1. Liu S
    2. Brind’Amour J
    3. Karimi MM
    4. Shirane K
    5. Bogutz A
    6. Lefebvre L
    7. Sasaki H
    8. Shinkai Y
    9. Lorincz MC

    (2014) Setdb1 is required for germline development and silencing of H3K9me3-marked endogenous retroviruses in primordial germ cells

    Genes & Development 28:2041–2055.

    https://doi.org/10.1101/gad.244848.114

    • Google Scholar
39. 1. Macfarlan TS
    2. Gifford WD
    3. Agarwal S
    4. Driscoll S
    5. Lettieri K
    6. Wang J
    7. Andrews SE
    8. Franco L
    9. Rosenfeld MG
    10. Ren B
    11. Pfaff SL

    (2011) Endogenous retroviruses and neighboring genes are coordinately repressed by LSD1/KDM1A

    Genes & Development 25:594–607.

    https://doi.org/10.1101/gad.2008511

    • Google Scholar
40. 1. Macfarlan TS
    2. Gifford WD
    3. Driscoll S
    4. Lettieri K
    5. Rowe HM
    6. Bonanomi D
    7. Firth A
    8. Singer O
    9. Trono D
    10. Pfaff SL

    (2012) Embryonic stem cell potency fluctuates with endogenous retrovirus activity

    Nature 487:57–63.

    https://doi.org/10.1038/nature11244

    • Google Scholar
41. 1. Maksakova IA
    2. Romanish MT
    3. Gagnier L
    4. Dunn CA
    5. van de Lagemaat LN
    6. Mager DL

    (2006) Retroviral elements and their hosts: insertional mutagenesis in the mouse germ line

    PLoS Genetics 2:e2.

    https://doi.org/10.1371/journal.pgen.0020002

    • Google Scholar
42. 1. Maksakova IA
    2. Thompson PJ
    3. Goyal P
    4. Jones SJ
    5. Singh PB
    6. Karimi MM
    7. Lorincz MC

    (2013) Distinct roles of KAP1, HP1 and G9a/GLP in silencing of the two-cell-specific retrotransposon MERVL in mouse ES cells

    Epigenetics & Chromatin 6:.

    https://doi.org/10.1186/1756-8935-6-15

    • Google Scholar
43. 1. Margueron R
    2. Reinberg D

    (2011) The polycomb complex PRC2 and its mark in life

    Nature 469:343–349.

    https://doi.org/10.1038/nature09784

    • Google Scholar
44. 1. Marks H
    2. Kalkan T
    3. Menafra R
    4. Denissov S
    5. Jones K
    6. Hofemeister H
    7. Nichols J
    8. Kranz A
    9. Stewart AF
    10. Smith A
    11. Stunnenberg HG

    (2012) The transcriptional and epigenomic foundations of ground state pluripotency

    Cell 149:590–604.

    https://doi.org/10.1016/j.cell.2012.03.026

    • Google Scholar
45. 1. Matsui T
    2. Leung D
    3. Miyashita H
    4. Maksakova IA
    5. Miyachi H
    6. Kimura H
    7. Tachibana M
    8. Lorincz MC
    9. Shinkai Y

    (2010) Proviral silencing in embryonic stem cells requires the histone methyltransferase ESET

    Nature 464:927–931.

    https://doi.org/10.1038/nature08858

    • Google Scholar
46. 1. Mendenhall EM
    2. Koche RP
    3. Truong T
    4. Zhou VW
    5. Issac B
    6. Chi AS
    7. Ku M
    8. Bernstein BE

    (2010) GC-rich sequence elements recruit PRC2 in mammalian ES cells

    PLoS Genetics 6:e1001244.

    https://doi.org/10.1371/journal.pgen.1001244

    • Google Scholar
47. 1. Mikkelsen TS
    2. Ku M
    3. Jaffe DB
    4. Issac B
    5. Lieberman E
    6. Giannoukos G
    7. Alvarez P
    8. Brockman W
    9. Kim TK
    10. Koche RP
    11. Lee W
    12. Mendenhall E
    13. O'Donovan A
    14. Presser A
    15. Russ C
    16. Xie X
    17. Meissner A
    18. Wernig M
    19. Jaenisch R
    20. Nusbaum C
    21. Lander ES
    22. Bernstein BE

    (2007) Genome-wide maps of chromatin state in pluripotent and lineage-committed cells

    Nature 448:553–560.

    https://doi.org/10.1038/nature06008

    • Google Scholar
48. 1. Peters AHFM
    2. Kubicek S
    3. Mechtler K
    4. O'Sullivan RJ
    5. Derijck AAHA
    6. Perez-Burgos L
    7. Kohlmaier A
    8. Opravil S
    9. Tachibana M
    10. Shinkai Y
    11. Martens JHA
    12. Jenuwein T

    (2003) Partitioning and plasticity of repressive histone methylation states in mammalian chromatin

    Molecular Cell 12:1577–1589.

    https://doi.org/10.1016/S1097-2765(03)00477-5

    • Google Scholar
49. 1. Pezic D
    2. Manakov SA
    3. Sachidanandam R
    4. Aravin AA

    (2014) PiRNA pathway targets active LINE1 elements to establish the repressive H3K9me3 mark in germ cells

    Genes & Development 28:1410–1428.

    https://doi.org/10.1101/gad.240895.114

    • Google Scholar
50. 1. Quinlan AR
    2. Hall IM

    (2010) BEDTools: a flexible suite of utilities for comparing genomic features

    Bioinformatics 26:841–842.

    https://doi.org/10.1093/bioinformatics/btq033

    • Google Scholar
51. 1. Reichmann J
    2. Crichton JH
    3. Madej MJ
    4. Taggart M
    5. Gautier P
    6. Garcia-Perez JL
    7. Meehan RR
    8. Adams IR

    (2012) Microarray analysis of LTR retrotransposon silencing identifies Hdac1 as a regulator of retrotransposon expression in mouse embryonic stem cells

    PLoS Computational Biology 8:e1002486.

    https://doi.org/10.1371/journal.pcbi.1002486

    • Google Scholar
52. 1. Pilsner JR
    2. Lazarus AL
    3. Nam DH
    4. Letcher RJ
    5. Sonne C
    6. Dietz R
    7. Basu N

    (2010) Mercury-associated DNA hypomethylation in polar bear brains via the LUminometric methylation assay: a sensitive method to study epigenetics in wildlife

    Molecular Ecology 19:307–314.

    https://doi.org/10.1111/j.1365-294X.2009.04452.x

    • Google Scholar
53. 1. Robinson MD
    2. Oshlack A

    (2010) A scaling normalization method for differential expression analysis of RNA-seq data

    Genome Biology 11:R25.

    https://doi.org/10.1186/gb-2010-11-3-r25

    • Google Scholar
54. 1. Rollins RA
    2. Haghighi F
    3. Edwards JR
    4. Das R
    5. Zhang MQ
    6. Ju J
    7. Bestor TH

    (2006) Large-scale structure of genomic methylation patterns

    Genome Research 16:157–163.

    https://doi.org/10.1101/gr.4362006

    • Google Scholar
55. 1. Rowe HM
    2. Jakobsson J
    3. Mesnard D
    4. Rougemont J
    5. Reynard S
    6. Aktas T
    7. Maillard PV
    8. Layard-Liesching H
    9. Verp S
    10. Marquis J
    11. Spitz F
    12. Constam DB
    13. Trono D

    (2010) KAP1 controls endogenous retroviruses in embryonic stem cells

    Nature 463:237–240.

    https://doi.org/10.1038/nature08674

    • Google Scholar
56. 1. Saksouk N
    2. Barth TK
    3. Ziegler-Birling C
    4. Olova N
    5. Nowak A
    6. Rey E
    7. Mateos-Langerak J
    8. Urbach S
    9. Reik W
    10. Torres-Padilla ME
    11. Imhof A
    12. Déjardin J
    13. Simboeck E

    (2014) Redundant mechanisms to form silent chromatin at pericentromeric regions rely on BEND3 and DNA methylation

    Molecular Cell 56:580–594.

    https://doi.org/10.1016/j.molcel.2014.10.001

    • Google Scholar
57. 1. Schoeftner S
    2. Sengupta AK
    3. Kubicek S
    4. Mechtler K
    5. Spahn L
    6. Koseki H
    7. Jenuwein T
    8. Wutz A

    (2006) Recruitment of PRC1 function at the initiation of x inactivation independent of PRC2 and silencing

    The EMBO Journal 25:3110–3122.

    https://doi.org/10.1038/sj.emboj.7601187

    • Google Scholar
58. 1. Schulz R
    2. Woodfine K
    3. Menheniott TR
    4. Bourc'his D
    5. Bestor T
    6. Oakey RJ

    (2008)

    WAMIDEX: a web atlas of murine genomic imprinting and differential expression

    Epigenetics 3:89–96.

    • Google Scholar
59. 1. Seisenberger S
    2. Andrews S
    3. Krueger F
    4. Arand J
    5. Walter J
    6. Santos F
    7. Popp C
    8. Thienpont B
    9. Dean W
    10. Reik W

    (2012) The dynamics of genome-wide DNA methylation reprogramming in mouse primordial germ cells

    Molecular Cell 48:849–862.

    https://doi.org/10.1016/j.molcel.2012.11.001

    • Google Scholar
60. 1. Seisenberger S
    2. Peat JR
    3. Hore TA
    4. Santos F
    5. Dean W
    6. Reik W

    (2013) Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers

    Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 368:.

    https://doi.org/10.1098/rstb.2011.0330

    • Google Scholar
61. 1. Seki Y
    2. Hayashi K
    3. Itoh K
    4. Mizugaki M
    5. Saitou M
    6. Matsui Y

    (2005) Extensive and orderly reprogramming of genome-wide chromatin modifications associated with specification and early development of germ cells in mice

    Developmental Biology 278:440–458.

    https://doi.org/10.1016/j.ydbio.2004.11.025

    • Google Scholar
62. 1. Seki Y
    2. Yamaji M
    3. Yabuta Y
    4. Sano M
    5. Shigeta M
    6. Matsui Y
    7. Saga Y
    8. Tachibana M
    9. Shinkai Y
    10. Saitou M

    (2007) Cellular dynamics associated with the genome-wide epigenetic reprogramming in migrating primordial germ cells in mice

    Development 134:2627–2638.

    https://doi.org/10.1242/dev.005611

    • Google Scholar
63. 1. Smith ZD
    2. Chan MM
    3. Mikkelsen TS
    4. Gu H
    5. Gnirke A
    6. Regev A
    7. Meissner A

    (2012) A unique regulatory phase of DNA methylation in the early mammalian embryo

    Nature 484:339–344.

    https://doi.org/10.1038/nature10960

    • Google Scholar
64. 1. Song Q
    2. Decato B
    3. Hong EE
    4. Zhou M
    5. Fang F
    6. Qu J
    7. Garvin T
    8. Kessler M
    9. Zhou J
    10. Smith AD

    (2013) A reference methylome database and analysis pipeline to facilitate integrative and comparative epigenomics

    PloS One 8:e81148.

    https://doi.org/10.1371/journal.pone.0081148

    • Google Scholar
65. 1. Stadler MB
    2. Murr R
    3. Burger L
    4. Ivanek R
    5. Lienert F
    6. Schöler A
    7. van Nimwegen E
    8. Wirbelauer C
    9. Oakeley EJ
    10. Gaidatzis D
    11. Tiwari VK
    12. Schübeler D

    (2011) DNA-binding factors shape the mouse methylome at distal regulatory regions

    Nature 480:490–495.

    https://doi.org/10.1038/nature10716

    • Google Scholar
66. 1. Stocking C
    2. Kozak CA

    (2008) Murine endogenous retroviruses

    Cellular and Molecular Life Sciences 65:3383–3398.

    https://doi.org/10.1007/s00018-008-8497-0

    • Google Scholar
67. 1. Tachibana M
    2. Sugimoto K
    3. Nozaki M
    4. Ueda J
    5. Ohta T
    6. Ohki M
    7. Fukuda M
    8. Takeda N
    9. Niida H
    10. Kato H
    11. Shinkai Y

    (2002) G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis

    Genes & Development 16:1779–1791.

    https://doi.org/10.1101/gad.989402

    • Google Scholar
68. 1. Tanay A
    2. O'Donnell AH
    3. Damelin M
    4. Bestor TH

    (2007) Hyperconserved CpG domains underlie polycomb-binding sites

    Proceedings of the National Academy of Sciences of the United States of America 104:5521–5526.

    https://doi.org/10.1073/pnas.0609746104

    • Google Scholar
69. 1. Trapnell C
    2. Williams BA
    3. Pertea G
    4. Mortazavi A
    5. Kwan G
    6. van Baren MJ
    7. Salzberg SL
    8. Wold BJ
    9. Pachter L

    (2010) Transcript assembly and quantification by RNA-seq reveals unannotated transcripts and isoform switching during cell differentiation

    Nature Biotechnology 28:511–515.

    https://doi.org/10.1038/nbt.1621

    • Google Scholar
70. 1. Tsumura A
    2. Hayakawa T
    3. Kumaki Y
    4. Takebayashi S
    5. Sakaue M
    6. Matsuoka C
    7. Shimotohno K
    8. Ishikawa F
    9. Li E
    10. Ueda HR
    11. Nakayama J
    12. Okano M

    (2006) Maintenance of self-renewal ability of mouse embryonic stem cells in the absence of DNA methyltransferases Dnmt1, Dnmt3a and Dnmt3b

    Genes to Cells : Devoted to Molecular & Cellular Mechanisms 11:805–814.

    https://doi.org/10.1111/j.1365-2443.2006.00984.x

    • Google Scholar
71. 1. Walsh CP
    2. Chaillet JR
    3. Bestor TH

    (1998) Transcription of IAP endogenous retroviruses is constrained by cytosine methylation

    Nature Genetics 20:116–117.

    https://doi.org/10.1038/2413

    • Google Scholar
72. 1. Wang J
    2. Xie G
    3. Singh M
    4. Ghanbarian AT
    5. Raskó T
    6. Szvetnik A
    7. Cai H
    8. Besser D
    9. Prigione A
    10. Fuchs NV
    11. Schumann GG
    12. Chen W
    13. Lorincz MC
    14. Ivics Z
    15. Hurst LD
    16. Izsvák Z
    17. Besser D
    18. Prigione A
    19. Fuchs NV

    (2014) Primate-specific endogenous retrovirus-driven transcription defines naive-like stem cells

    Nature 516:405–409.

    https://doi.org/10.1038/nature13804

    • Google Scholar
73. 1. Ying QL
    2. Wray J
    3. Nichols J
    4. Batlle-Morera L
    5. Doble B
    6. Woodgett J
    7. Cohen P
    8. Smith A

    (2008) The ground state of embryonic stem cell self-renewal

    Nature 453:519–523.

    https://doi.org/10.1038/nature06968

    • Google Scholar
74. 1. Zamudio N
    2. Bourc'his D

    (2010) Transposable elements in the mammalian germline: a comfortable niche or a deadly trap?

    Heredity 105:92–104.

    https://doi.org/10.1038/hdy.2010.53

    • Google Scholar
75. 1. Zamudio N
    2. Barau J
    3. Teissandier A
    4. Walter M
    5. Borsos M
    6. Servant N
    7. Bourc'his D

    (2015) DNA methylation restrains transposons from adopting a chromatin signature permissive for meiotic recombination

    Genes & Development 29:1256–1270.

    https://doi.org/10.1101/gad.257840.114

    • Google Scholar
76. 1. Zhang Y
    2. Liu T
    3. Meyer CA
    4. Eeckhoute J
    5. Johnson DS
    6. Bernstein BE
    7. Nusbaum C
    8. Myers RM
    9. Brown M
    10. Li W
    11. Liu XS

    (2008) Model-based analysis of ChIP-seq (mACS)

    Genome Biology 9:R137.

    https://doi.org/10.1186/gb-2008-9-9-r137

    • Google Scholar

Author details

1. Marius Walter

   1. Department of Genetics and Developmental Biology, Institut Curie, Paris, France
   2. Paris Science Lettres Research University
   3. UMR3215, CNRS, Paris, France
   4. U934, Inserm, Paris, France

   Contribution

   MW, Performed all the experiments, at the exception of the immunofluorescence studies, Conducted bioinformatics analyses, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

2. Aurélie Teissandier

   1. Department of Genetics and Developmental Biology, Institut Curie, Paris, France
   2. UMR3215, CNRS, Paris, France
   3. U934, Inserm, Paris, France
   4. Paris Science Lettres Research University
   5. Bioinformatics, Biostatistics, Epidemiology and Computational Systems Biology of Cancer, Institut Curie, Paris, France
   6. Mines Paris Tech, Paris, France
   7. U900, Inserm, Paris, France

   Contribution

   AT, Conducted bioinformatics analyses, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

3. Raquel Pérez-Palacios

   1. Department of Genetics and Developmental Biology, Institut Curie, Paris, France
   2. UMR3215, CNRS, Paris, France
   3. U934, Inserm, Paris, France
   4. Paris Science Lettres Research University

   Contribution

   RPP, Performed the immunofluorescence studies, Acquisition of data

   Competing interests

   The authors declare that no competing interests exist.

4. Déborah Bourc'his

   1. Department of Genetics and Developmental Biology, Institut Curie, Paris, France
   2. UMR3215, CNRS, Paris, France
   3. U934, Inserm, Paris, France
   4. Paris Science Lettres Research University

   Contribution

   DB, Conception and design, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   deborah.bourchis@curie.fr

   Competing interests

   The authors declare that no competing interests exist.

• 15,274

  views

• 2,393

  downloads

• 241

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.