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

Zamudio, Natasha; Barau, Joan; Teissandier, Aurélie; Walter, Marius; Borsos, Máté; Servant, Nicolas; Bourc’his, Déborah

doi:10.1101/gad.257840.114

Cited by 154 publications

(156 citation statements)

References 73 publications

Supporting

Mentioning

137

Contrasting

Order By: Relevance

“…The pattern of H3K27me3 is especially interesting because it is occasionally symmetrical on each side of the SC, which hints at an association with defined regions of the genome (33). These clusters may be selected to escape recombination, similar to how DNA methylation was suggested to prevent recombination in transposon sequences (34). Another possible hypothesis is that H3K27me3 clusters may be involved in the formation of the SC itself (35).…”

Section: Discussionmentioning

confidence: 99%

Superresolution imaging reveals structurally distinct periodic patterns of chromatin along pachytene chromosomes

Prakash

Fournier

Redl

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

During meiosis, homologous chromosomes associate to form the synaptonemal complex (SC), a structure essential for fertility. Information about the epigenetic features of chromatin within this structure at the level of superresolution microscopy is largely lacking. We combined single-molecule localization microscopy (SMLM) with quantitative analytical methods to describe the epigenetic landscape of meiotic chromosomes at the pachytene stage in mouse oocytes. DNA is found to be nonrandomly distributed along the length of the SC in condensed clusters. Periodic clusters of repressive chromatin [trimethylation of histone H3 at lysine (Lys) 27 (H3K27me3)] are found at 500-nm intervals along the SC, whereas one of the ends of the SC displays a large and dense cluster of centromeric histone mark [trimethylation of histone H3 at Lys 9 (H3K9me3)]. Chromatin associated with active transcription [trimethylation of histone H3 at Lys 4 (H3K4me3)] is arranged in a radial hair-like loop pattern emerging laterally from the SC. These loops seem to be punctuated with small clusters of H3K4me3 with an average spread larger than their periodicity. Our findings indicate that the nanoscale structure of the pachytene chromosomes is constrained by periodic patterns of chromatin marks, whose function in recombination and higher order genome organization is yet to be elucidated.

show abstract

Section: Discussionmentioning

confidence: 99%

Superresolution imaging reveals structurally distinct periodic patterns of chromatin along pachytene chromosomes

Prakash

Fournier

Redl

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…However, the sheer abundance of preexisting L1 copies in the mouse genome presents a formidable technical challenge to quantifying the frequency and magnitude of de novo insertions. Indeed, this technical barrier has prevented the characterization of the extent and timing of retrotransposition during germ-cell development (22). For example, even the most rudimentary information is unavailable as to what extent retrotransposition occurs in piRNA pathway mutants and whether an increase of insertions, if any, is concurrent with the meiotic phenotype.…”

Section: Significancementioning

confidence: 99%

Intact piRNA pathway prevents L1 mobilization in male meiosis

Newkirk

Lee

Grandi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The PIWI-interacting RNA (piRNA) pathway is essential for retrotransposon silencing. In piRNA-deficient mice, L1-overexpressing male germ cells exhibit excessive DNA damage and meiotic defects. It remains unknown whether L1 expression simply highlights piRNA deficiency or actually drives the germ-cell demise. Specifically, the sheer abundance of genomic L1 copies prevents reliable quantification of new insertions. Here, we developed a codon-optimized L1 transgene that is controlled by an endogenous mouse L1 promoter. Importantly, DNA methylation dynamics of a single-copy transgene were indistinguishable from those of endogenous L1s. Analysis of Mov10l1 −/− testes established that de novo methylation of the L1 transgene required the intact piRNA pathway. Consistent with loss of DNA methylation and programmed reduction of H3K9me2 at meiotic onset, the transgene showed 1,400-fold increase in RNA expression and consequently 70-fold increase in retrotransposition in postnatal day 14 Mov10l1 −/− germ cells compared with the wildtype. Analysis of adult Mov10l1 −/− germ-cell fractions indicated a stage-specific increase of retrotransposition in the early meiotic prophase. However, extrapolation of the transgene data to endogenous L1s suggests that it is unlikely insertional mutagenesis alone accounts for the Mov10l1 −/− phenotype. Indeed, pharmacological inhibition of reverse transcription did not rescue the meiotic defect. Cumulatively, these results establish the occurrence of productive L1 mobilization in the absence of an intact piRNA pathway but leave open the possibility of processes preceding L1 integration in triggering meiotic checkpoints and germ-cell death. Additionally, our data suggest that many heritable L1 insertions originate from individuals with partially compromised piRNA defense.LINE-1 reporter transgene | meiotic arrest | PIWI-interacting RNA | retrotransposition | spermatogenesis T he bulk of mammalian genomes are made up of transposable elements, the majority of which are retrotransposons (1). Retrotransposons are classified into long-interspersed elements (LINEs), short-interspersed elements (SINEs), and LTR retrotransposons, which collectively account for 43% and 37% of the human and mouse genomes, respectively (2). Retrotransposons amplify in the genome through an RNA intermediate, a process termed retrotransposition. LINEs are autonomous elements. An intact, full-length LINE-1 (L1) encodes two ORFs (i.e., ORF1 and ORF2); both are required for L1 mobilization (3). SINEs are nonautonomous elements and rely on L1's proteins for propagation in the genome (4). LTR retrotransposons are autonomous but appear to be inactivated in the human genome (5). Retrotransposition endangers the integrity of both somatic and germline genomes through insertional mutagenesis. In somatic tissues, both elevated L1 expression and retrotransposition have been strongly associated with many types of human cancers (6, 7). In a few cases, specific retrotransposition events (i.e., insertions) have been determined to drive t...

show abstract

“…The negative impact of LTR transposons on recombination in wheat could also be attributed to their associated epigenetic patterns which condense DNA and lock the regions, preventing their accessibility to the recombination machinery. As an example, in mouse, methylation leads to DNA conformation which prevents transposons from adopting a permissive chromatin structure for meiotic recombination (Zamudio et al 2015). Finally, in barley, pericentromeric regions with low recombination rates bear LTR retrotransposons that carry the epigenetic landmarks H3K9me2 and H3K27me1 which establish a constitutive heterochromatic state (Baker et al 2015).…”

Section: Retrotransposons Associate With Reduced Recombination Ratementioning

confidence: 99%

“…In Arabidopsis, DNA methylation can silence CO hotspots and plays an essential role in forming domains of meiotic recombination along chromosomes (Yelina et al 2015). Recently, a study in mouse revealed that DNA methylation can prevent transposons from adopting chromatin characteristics amenable to meiotic recombination (Zamudio et al 2015), underlying the importance of DNA conformation and the likely role of epigenetic marks on recombination.…”

mentioning

confidence: 99%

High-Resolution Mapping of Crossover Events in the Hexaploid Wheat Genome Suggests a Universal Recombination Mechanism

et al. 2017

View full text Add to dashboard Cite

During meiosis, crossovers (COs) create new allele associations by reciprocal exchange of DNA. In bread wheat (Triticum aestivum L.), COs are mostly limited to subtelomeric regions of chromosomes, resulting in a substantial loss of breeding efficiency in the proximal regions, though these regions carry 60-70% of the genes. Identifying sequence and/or chromosome features affecting recombination occurrence is thus relevant to improve and drive recombination. Using the recent release of a reference sequence of chromosome 3B and of the draft assemblies of the 20 other wheat chromosomes, we performed fine-scale mapping of COs and revealed that 82% of COs located in the distal ends of chromosome 3B representing 19% of the chromosome length. We used 774 SNPs to genotype 180 varieties representative of the Asian and European genetic pools and a segregating population of 1270 F 6 lines. We observed a common location for ancestral COs (predicted through linkage disequilibrium) and the COs derived from the segregating population. We delineated 73 small intervals (,26 kb) on chromosome 3B that contained 252 COs. We observed a significant association of COs with genic features (73 and 54% in recombinant and nonrecombinant intervals, respectively) and with those expressed during meiosis (67% in recombinant intervals and 48% in nonrecombinant intervals). Moreover, while the recombinant intervals contained similar amounts of retrotransposons and DNA transposons (42 and 53%), nonrecombinant intervals had a higher level of retrotransposons (63%) and lower levels of DNA transposons (28%). Consistent with this, we observed a higher frequency of a DNA motif specific to the TIR-Mariner DNA transposon in recombinant intervals. KEYWORDS recombination; meiosis; bread wheat; linkage disequilibrium; transposon; hotspot; sequence motif M EIOTIC recombination is a process that allows reshuffling of diversity by the reciprocal exchange of DNA called a crossover (CO). This phenomenon is conserved in most eukaryotes (for a review see Mercier et al. 2015) and follows the formation of a double-strand break (DSB) of DNA generated by the topoisomerase SPO11 complex. However, the number of DSBs is at least 10-to 50-fold greater than the number of COs which rarely exceeds three per bivalent chromosome per meiosis (Mercier et al. 2015). This paucity of COs per meiosis with regards to the number of DSBs suggests the existence of a tight control and regulation of recombination in plants that promote DSB repair in a manner that does not lead to COs. For example, the study of the two helicases AtFANCM and RECQ4 (AtRECQ4A and AtRECQ4B) (Crismani et al. 2012;Knoll et al. 2012;Girard et al. 2014;Séguéla-Arnaud et al. 2015) revealed three-and sixfold CO frequency increases in the Atfancm single mutant and the Atrecq4a/Atrecq4b double mutant, respectively, compared to the wild type. These increases result from additional COs from the class-II pathway which suggests that FANCM and RECQ4 prevent CO formation and direct recombination intermediates towar...

show abstract

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

Cited by 154 publications

References 73 publications

Superresolution imaging reveals structurally distinct periodic patterns of chromatin along pachytene chromosomes

Superresolution imaging reveals structurally distinct periodic patterns of chromatin along pachytene chromosomes

Intact piRNA pathway prevents L1 mobilization in male meiosis

High-Resolution Mapping of Crossover Events in the Hexaploid Wheat Genome Suggests a Universal Recombination Mechanism

Contact Info

Product

Resources

About