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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    • "To gain insights across the entire human germline cycle, we included published BS-seq data of human sperm and ICM (Guo et al., 2014; Molaro et al., 2011). As a result of de novo methylation, sperm dramatically gained methylation to 87% from $4% in Wk9 male hPGCs (Figures 4A and 4C). "
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    ABSTRACT: Resetting of the epigenome in human primordial germ cells (hPGCs) is critical for development. We show that the transcriptional program of hPGCs is distinct from that in mice, with co-expression of somatic specifiers and naive pluripotency genes TFCP2L1 and KLF4. This unique gene regulatory network, established by SOX17 and BLIMP1, drives comprehensive germline DNA demethylation by repressing DNA methylation pathways and activating TET-mediated hydroxymethylation. Base-resolution methylome analysis reveals progressive DNA demethylation to basal levels in week 5-7 in vivo hPGCs. Concurrently, hPGCs undergo chromatin reorganization, X reactivation, and imprint erasure. Despite global hypomethylation, evolutionarily young and potentially hazardous retroelements, like SVA, remain methylated. Remarkably, some loci associated with metabolic and neurological disorders are also resistant to DNA demethylation, revealing potential for transgenerational epigenetic inheritance that may have phenotypic consequences. We provide comprehensive insight on early human germline transcriptional network and epigenetic reprogramming that subsequently impacts human development and disease. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell 06/2015; 161(6):1453-1467. DOI:10.1016/j.cell.2015.04.053 · 32.24 Impact Factor
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    • "Cells in these compartments have previously been observed to segregate similarly based upon expression patterns (Charafe-Jauffret et al., 2006; dos Santos et al., 2013) As with other somatic cell types analyzed to date, mammary methylomes exhibit discrete intervals of hypomethylation, punctuating the globally high background methylation. Using a previously described method (Hodges et al., 2011; Molaro et al., 2011; Schlesinger et al., 2013), we identified the set of hypomethylated regions (HMRs) in each methylome. HMRs correspond to regions with low methylation in the underlying population of cells and are a suitable basis for globally describing epigenetic alterations associated with mammary development. "
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    ABSTRACT: Pregnancy is the major modulator of mammary gland activity. It induces a tremendous expansion of the mammary epithelium and the generation of alveolar structures for milk production. Anecdotal evidence from multiparous humans indicates that the mammary gland may react less strongly to the first pregnancy than it does to subsequent pregnancies. Here, we verify that the mouse mammary gland responds more robustly to a second pregnancy, indicating that the gland retains a long-term memory of pregnancy. A comparison of genome-wide profiles of DNA methylation in isolated mammary cell types reveals substantial and long-lasting alterations. Since these alterations are maintained in the absence of the signal that induced them, we term them epigenetic. The majority of alterations in DNA methylation affect sites occupied by the Stat5a transcription factor and mark specific genes that are upregulated during pregnancy. We postulate that the epigenetic memory of a first pregnancy primes the activation of gene expression networks that promote mammary gland function in subsequent reproductive cycles. More broadly, our data indicate that physiological experience can broadly alter epigenetic states, functionally modifying the capacity of the affected cells to respond to later stimulatory events. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 05/2015; 11(7). DOI:10.1016/j.celrep.2015.04.015 · 8.36 Impact Factor
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    • "Two-state beta-binomial HMM was adapted from a previously described method (Molaro et al. 2011) to segment regions into methyltransferase accessible regions (MARs) and methyltransferase protected regions (MPRs), based on GCH methylation in HCT116 and DKO1 cells. Training of the model was performed independently for each biological replicate. "
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    ABSTRACT: The holistic role of DNA methylation in the organization of the cancer epigenome is not well understood. Here we perform a comprehensive, high-resolution analysis of chromatin structure to compare the landscapes of HCT116 colon cancer cells and a DNA methylation-deficient derivative. The NOMe-seq accessibility assay unexpectedly revealed symmetrical and transcription-independent nucleosomal phasing across active, poised, and inactive genomic elements. DNA methylation abolished this phasing primarily at enhancers and CpG island (CGI) promoters, with little effect on insulators and non-CGI promoters. Abolishment of DNA methylation led to the context-specific reestablishment of the poised and active states of normal colon cells, which were marked in methylation-deficient cells by distinct H3K27 modifications and the presence of either well-phased nucleosomes or nucleosome-depleted regions, respectively. At higher-order genomic scales, we found that long, H3K9me3-marked domains had lower accessibility, consistent with a more compact chromatin structure. Taken together, our results demonstrate the nuanced and context-dependent role of DNA methylation in the functional, multiscale organization of cancer epigenomes. © 2015 Lay et al.; Published by Cold Spring Harbor Laboratory Press.
    Genome Research 03/2015; 25(4). DOI:10.1101/gr.183368.114 · 14.63 Impact Factor
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