DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (original) (raw)
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Epigenetic Remodeling in Male Germline Development
Stem cells international, 2016
In mammals, germ cells guarantee the inheritance of genetic and epigenetic information across generations and are the origin of a new organism. During embryo development, the blastocyst is formed in the early stage, is comprised of an inner cell mass which is pluripotent, and could give rise to the embryonic stem cells (ESCs). The inner cell mass undergoes demethylation processes and will reestablish a methylated state that is similar to that of somatic cells later in epiblast stage. Primordial germ cells (PGCs) will be formed very soon and accompanied by the process of genome-wide demethylation. With the input of male sex determination genes, spermatogonial stem cells (SSCs) are generated and undergo the process of spermatogenesis. Spermatogenesis is a delicately regulated process in which various regulations are launched to guarantee normal mitosis and meiosis in SSCs. During all these processes, especially during spermatid development, DNA methylation profile and histone modifica...
Developmental acquisition of genome-wide DNA methylation occurs prior to meiosis in male germ cells
Developmental Biology, 2007
The development of germ cells is a highly ordered process that begins during fetal growth and is completed in the adult. Epigenetic modifications that occur in germ cells are important for germ cell function and for post-fertilization embryonic development. We have previously shown that male germ cells in the adult mouse have a highly distinct epigenetic state, as revealed by a unique genome-wide pattern of DNA methylation. Although it is known that these patterns begin to be established during fetal life, it is not known to what extent DNA methylation is modified during spermatogenesis. We have used restriction landmark genomic scanning (RLGS) and other techniques to examine DNA methylation at multiple sites across the genome during postnatal germ cell development in the mouse. Although a significant proportion of the distinct germ cell pattern is acquired prior to the type A spermatogonial stage, we find that both de novo methylation and demethylation occur during spermatogenesis, mainly in spermatogonia and spermatocytes in early meiotic prophase I. Alterations include predominantly non-CpG island sequences from both unique loci and repetitive elements. These modifications are progressive and are almost exclusively completed by the end of the pachytene spermatocyte stage. These studies better define the developmental timing of genome-wide DNA methylation pattern acquisition during male germ cell development.
Epigenetic Reprogramming in Mice and Humans: From Fertilization to Primordial Germ Cell Development
Cells, 2023
In this review, advances in the understanding of epigenetic reprogramming from fertilization to the development of primordial germline cells in a mouse and human embryo are discussed. To gain insights into the molecular underpinnings of various diseases, it is essential to comprehend the intricate interplay between genetic, epigenetic, and environmental factors during cellular reprogramming and embryonic differentiation. An increasing range of diseases, including cancer and developmental disorders, have been linked to alterations in DNA methylation and histone modifications. Global epigenetic reprogramming occurs in mammals at two stages: post-fertilization and during the development of primordial germ cells (PGC). Epigenetic reprogramming after fertilization involves rapid demethylation of the paternal genome mediated through active and passive DNA demethylation, and gradual demethylation in the maternal genome through passive DNA demethylation. The de novo DNA methyltransferase enzymes, Dnmt3a and Dnmt3b, restore DNA methylation beginning from the blastocyst stage until the formation of the gastrula, and DNA maintenance methyltransferase, Dnmt1, maintains methylation in the somatic cells. The PGC undergo a second round of global demethylation after allocation during the formative pluripotent stage before gastrulation, where the imprints and the methylation marks on the transposable elements known as retrotransposons, including long interspersed nuclear elements (LINE-1) and intracisternal A-particle (IAP) elements are demethylated as well. Finally, DNA methylation is restored in the PGC at the implantation stage including sex-specific imprints corresponding to the sex of the embryo. This review introduces a novel perspective by uncovering how toxicants and stress stimuli impact the critical period of allocation during formative pluripotency, potentially influencing both the quantity and quality of PGCs. Furthermore, the comprehensive comparison of epigenetic events between mice and humans breaks new ground, empowering researchers to make informed decisions regarding the suitability of mouse models for their experiments.
Developmental Biology, 2004
The acquisition of genomic methylation in the male germ line is initiated prenatally in diploid gonocytes, while DNA methylation in the female germ line is initiated postnatally in growing oocytes. We compared the temporal expression patterns of the DNA methyltransferases, DNMT1, DNMT3a, DNMT3b, and DNMT3l in the male and female germ lines. DNMT1 expression was examined by immunocytochemistry and Northerns with an emphasis on the prenatal period. In the female, there is a gradual down-regulation of DNMT1 protein in prenatal meiotic prophase I oocytes that is not associated with the production of an untranslated transcript, as it is in the male; these results suggest that the mechanism of meiotic down-regulation differs between the sexes. In the male, DNMT1 is unlikely to play a role in the prenatal acquisition of germ line methylation patterns since it is down-regulated in gonocytes between 14.5 and 18.5 days of gestation and is absent at the time of initiation of DNA methylation. To search for candidate DNMTs that could be involved in establishing methylation patterns in both germ lines, real-time RT-PCR was used to simultaneously study the expression profiles of the three DNMT3 enzymes in developing testes and ovaries; DNMT1 expression was included as a control. Expression profiles of DNMT3a and DNMT3l provide support for an interaction of the two enzymes during prenatal germ cell development and de novo methylation in the male. DNMT3l is the predominant DNMT3 enzyme expressed at high levels in the postnatal female germ line at the time of acquisition of DNA methylation patterns. DNMT1 and DNMT3b expression levels peak concomitantly, shortly after birth in the male, consistent with a role in the maintenance of methylation patterns in proliferating spermatogonia. Together, the results provide clues to specific roles for the different DNMT family members in de novo and maintenance methylation in the developing testis and ovary. D
Establishment and functions of DNA methylation in the germline
Epigenomics, 2016
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.
Epigenetics refers to covalent modifications of DNA and core histones that regulate gene activity without altering DNA sequence. To date, the best-characterized DNA modification associated with the modulation of gene activity is methylation of cytosine residues within CpG dinucleotides. Human disorders associated with epigenetic abnormalities include rare imprinting diseases, molar pregnancies, and childhood cancers. Germ cell development and early embryo development are critical times when epigenetic patterns are initiated or maintained. This review focuses on the epigenetic modification DNA methylation and discusses recent progress that has been made in understanding when and how epigenetic patterns are differentially established in the male and female germlines, the mouse, and human disorders associated with abnormalities in epigenetic programming in germ cells and early embryos, as well as genetic and other modulators (e.g. nutrition and drugs) of reproductive epigenetic events.