Sperm Methylation Profiles Reveal Features of Epigenetic Inheritance and Evolution in Primates

Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA.
Cell (Impact Factor: 32.24). 09/2011; 146(6):1029-41. DOI: 10.1016/j.cell.2011.08.016
Source: PubMed


During germ cell and preimplantation development, mammalian cells undergo nearly complete reprogramming of DNA methylation patterns. We profiled the methylomes of human and chimp sperm as a basis for comparison to methylation patterns of ESCs. Although the majority of promoters escape methylation in both ESCs and sperm, the corresponding hypomethylated regions show substantial structural differences. Repeat elements are heavily methylated in both germ and somatic cells; however, retrotransposons from several subfamilies evade methylation more effectively during male germ cell development, whereas other subfamilies show the opposite trend. Comparing methylomes of human and chimp sperm revealed a subset of differentially methylated promoters and strikingly divergent methylation in retrotransposon subfamilies, with an evolutionary impact that is apparent in the underlying genomic sequence. Thus, the features that determine DNA methylation patterns differ between male germ cells and somatic cells, and elements of these features have diverged between humans and chimpanzees.

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    • "HMRs were identified as previously described[22]. Briefly, the raw methylated and unmethylated read counts of each CpG site, modeled with a beta-binomial distribution, provided the input for a hidden Markov segmentation model with two states (high and low methylation). "
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    ABSTRACT: Background One of the hallmarks of cancer is the disruption of gene expression patterns. Many molecular lesions contribute to this phenotype, and the importance of aberrant DNA methylation profiles is increasingly recognized. Much of the research effort in this area has examined proximal promoter regions and epigenetic alterations at other loci are not well characterized. Results Using whole genome bisulfite sequencing to examine uncharted regions of the epigenome, we identify a type of far-reaching DNA methylation alteration in cancer cells of the distal regulatory sequences described as super-enhancers. Human tumors undergo a shift in super-enhancer DNA methylation profiles that is associated with the transcriptional silencing or the overactivation of the corresponding target genes. Intriguingly, we observe locally active fractions of super-enhancers detectable through hypomethylated regions that suggest spatial variability within the large enhancer clusters. Functionally, the DNA methylomes obtained suggest that transcription factors contribute to this local activity of super-enhancers and that trans-acting factors modulate DNA methylation profiles with impact on transforming processes during carcinogenesis. Conclusions We develop an extensive catalogue of human DNA methylomes at base resolution to better understand the regulatory functions of DNA methylation beyond those of proximal promoter gene regions. CpG methylation status in normal cells points to locally active regulatory sites at super-enhancers, which are targeted by specific aberrant DNA methylation events in cancer, with putative effects on the expression of downstream genes.
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    • "To increase the fraction of the epigenetic coverage, we also included an analysis of the methylation level of Sata, is largely confined to chromosome centromeres, whereas LINE-1 and Alu are interspersed throughout the genome. In contrast to the similarity of transposable sequence percent methylation in somatic and germ cells, Sata methylation level appeared to be lower in sperm than in PBLsFabris et al., 2011], confirming previous reports[Weisenberger et al., 2005;Yamagata et al., 2007;Molaro et al., 2011]. An association has been proposed between the hypomethylation of pericentromeric DNA in germ cells and a germline specific architecture of the centromere influencing gene expression and/or chromosome segregation in meio- sis[Yamagata et al., 2007]. "
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    • "The normal sperm epigenome has been described in detail (Hammoud et al. 2009, 2014; Molaro et al. 2011) and contains important features. First, similar to the stem cell epigenome, the promoter regions of both bivalently and monovalently marked developmental genes in sperm are hypomethylated compared to somatic cells (Molaro et al. 2011). These observations further support the hypothesis of a poised sperm epigenome , transcriptionally silenced, but 'poised' to facilitate rapid initiation of transcription, an observation confirmed in the zebrafish (Wu et al. 2011). "
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