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Wolf Reik - One of the best experts on this subject based on the ideXlab platform.
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Forget the Parents: Epigenetic Reprogramming in Human Germ Cells
Cell, 2015Co-Authors: Ferdinand Von Meyenn, Wolf ReikAbstract:Epigenetic Reprogramming in the germline resets genomic potential and erases Epigenetic memory. Three studies by Gkountela et al., Guo et al., and Tang et al. analyze the transcriptional and Epigenetic landscape of human primordial germ cells, revealing a unique transcriptional network and progressive and conserved global erasure of DNA methylation.
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Promoter DNA methylation couples genome-defence mechanisms to Epigenetic Reprogramming in the mouse germline
Development (Cambridge England), 2012Co-Authors: Jamie A. Hackett, Wolf Reik, M.a. Surani, Miguel R. Branco, James P. Reddington, Colm E. Nestor, Donncha S. Dunican, Judith Reichmann, Ian R. Adams, Richard R. MeehanAbstract:Mouse primordial germ cells (PGCs) erase global DNA methylation (5mC) as part of the comprehensive Epigenetic Reprogramming that occurs during PGC development. 5mC plays an important role in maintaining stable gene silencing and repression of transposable elements (TE) but it is not clear how the extensive loss of DNA methylation impacts on gene expression and TE repression in developing PGCs. Using a novel Epigenetic disruption and recovery screen and genetic analyses, we identified a core set of germline-specific genes that are dependent exclusively on promoter DNA methylation for initiation and maintenance of developmental silencing. These gene promoters appear to possess a specialised chromatin environment that does not acquire any of the repressive H3K27me3, H3K9me2, H3K9me3 or H4K20me3 histone modifications when silenced by DNA methylation. Intriguingly, this methylation-dependent subset is highly enriched in genes with roles in suppressing TE activity in germ cells. We show that the mechanism for developmental regulation of the germline genome-defence genes involves DNMT3B-dependent de novo DNA methylation. These genes are then activated by lineage-specific promoter demethylation during distinct global Epigenetic Reprogramming events in migratory (~E8.5) and post-migratory (E10.5-11.5) PGCs. We propose that genes involved in genome defence are developmentally regulated primarily by promoter DNA methylation as a sensory mechanism that is coupled to the potential for TE activation during global 5mC erasure, thereby acting as a failsafe to ensure TE suppression and maintain genomic integrity in the germline.
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Epigenetic Reprogramming in plant and animal development
Science, 2010Co-Authors: Suhua Feng, Steven E Jacobsen, Wolf ReikAbstract:Epigenetic modifications of the genome are generally stable in somatic cells of multicellular organisms. In germ cells and early embryos, however, Epigenetic Reprogramming occurs on a genome-wide scale, which includes demethylation of DNA and remodeling of histones and their modifications. The mechanisms of genome-wide erasure of DNA methylation, which involve modifications to 5-methylcytosine and DNA repair, are being unraveled. Epigenetic Reprogramming has important roles in imprinting, the natural as well as experimental acquisition of totipotency and pluripotency, control of transposons, and Epigenetic inheritance across generations. Small RNAs and the inheritance of histone marks may also contribute to Epigenetic inheritance and Reprogramming. Reprogramming occurs in flowering plants and in mammals, and the similarities and differences illuminate developmental and reproductive strategies.
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Global Mapping of DNA Methylation in Mouse Promoters Reveals Epigenetic Reprogramming of Pluripotency Genes
PLoS genetics, 2008Co-Authors: Cassandra R. Farthing, Wendy Dean, Gabriella Ficz, Cf Chan, Simon Andrews, Myriam Hemberger, Wolf ReikAbstract:DNA methylation patterns are reprogrammed in primordial germ cells and in preimplantation embryos by demethylation and subsequent de novo methylation. It has been suggested that Epigenetic Reprogramming may be necessary for the embryonic genome to return to a pluripotent state. We have carried out a genome-wide promoter analysis of DNA methylation in mouse embryonic stem (ES) cells, embryonic germ (EG) cells, sperm, trophoblast stem (TS) cells, and primary embryonic fibroblasts (pMEFs). Global clustering analysis shows that methylation patterns of ES cells, EG cells, and sperm are surprisingly similar, suggesting that while the sperm is a highly specialized cell type, its promoter epigenome is already largely reprogrammed and resembles a pluripotent state. Comparisons between pluripotent tissues and pMEFs reveal that a number of pluripotency related genes, including Nanog, Lefty1 and Tdgf1, as well as the nucleosome remodeller Smarcd1, are hypomethylated in stem cells and hypermethylated in differentiated cells. Differences in promoter methylation are associated with significant differences in transcription levels in more than 60% of genes analysed. Our comparative approach to promoter methylation thus identifies gene candidates for the regulation of pluripotency and Epigenetic Reprogramming. While the sperm genome is, overall, similarly methylated to that of ES and EG cells, there are some key exceptions, including Nanog and Lefty1, that are highly methylated in sperm. Nanog promoter methylation is erased by active and passive demethylation after fertilisation before expression commences in the morula. In ES cells the normally active Nanog promoter is silenced when targeted by de novo methylation. Our study suggests that Reprogramming of promoter methylation is one of the key determinants of the Epigenetic regulation of pluripotency genes. Epigenetic Reprogramming in the germline prior to fertilisation and the Reprogramming of key pluripotency genes in the early embryo is thus crucial for transmission of pluripotency.
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Safeguarding parental identity: Dnmt1 maintains imprints during Epigenetic Reprogramming in early embryogenesis
Genes & development, 2008Co-Authors: Miguel R. Branco, Masaaki Oda, Wolf ReikAbstract:During early mammalian embryogenesis, the genome undergoes global Epigenetic Reprogramming, losing most of its methylation before re-establishing it de novo at implantation. However, faithful maintenance of methylation at imprinted genes during this process is vital for embryonic development, but the DNA methyltransferase responsible for this maintenance has remained unknown. In this issue of Genes & Development, Hirasawa and colleagues (pp. 1607-1616) show that Dnmt1, and not Dnmt3a or Dnmt3b, maintains methylation at genomic imprints during preimplantation development.
M.a. Surani - One of the best experts on this subject based on the ideXlab platform.
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Primordial germ-cell development and Epigenetic Reprogramming in mammals.
Current topics in developmental biology, 2013Co-Authors: Harry G. Leitch, Walfred W.c. Tang, M.a. SuraniAbstract:Primordial germ cells (PGCs) are the embryonic precursors of the gametes and represent the founder cells of the germline. Specification of PGCs is a critical divergent point during embryogenesis. Whereas the somatic lineages will ultimately perish, cells of the germline have the potential to form a new individual and hence progress to the next generation. It is therefore critical that the genome emerges intact and carrying the appropriate Epigenetic information during its passage through the germline. To ensure this fidelity of transmission, PGC development encompasses extensive Epigenetic Reprogramming. The low cell numbers and relative inaccessibility of PGCs present a challenge to those seeking mechanistic understanding of the crucial developmental and Epigenetic processes in this most fascinating of lineages. Here, we present an overview of PGC development in the mouse and compare this with the limited information available for other mammalian species. We believe that a comparative approach will be increasingly important to uncover the extent to which mechanisms are conserved and reveal the critical steps during PGC development in humans.
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Promoter DNA methylation couples genome-defence mechanisms to Epigenetic Reprogramming in the mouse germline
Development (Cambridge England), 2012Co-Authors: Jamie A. Hackett, Wolf Reik, M.a. Surani, Miguel R. Branco, James P. Reddington, Colm E. Nestor, Donncha S. Dunican, Judith Reichmann, Ian R. Adams, Richard R. MeehanAbstract:Mouse primordial germ cells (PGCs) erase global DNA methylation (5mC) as part of the comprehensive Epigenetic Reprogramming that occurs during PGC development. 5mC plays an important role in maintaining stable gene silencing and repression of transposable elements (TE) but it is not clear how the extensive loss of DNA methylation impacts on gene expression and TE repression in developing PGCs. Using a novel Epigenetic disruption and recovery screen and genetic analyses, we identified a core set of germline-specific genes that are dependent exclusively on promoter DNA methylation for initiation and maintenance of developmental silencing. These gene promoters appear to possess a specialised chromatin environment that does not acquire any of the repressive H3K27me3, H3K9me2, H3K9me3 or H4K20me3 histone modifications when silenced by DNA methylation. Intriguingly, this methylation-dependent subset is highly enriched in genes with roles in suppressing TE activity in germ cells. We show that the mechanism for developmental regulation of the germline genome-defence genes involves DNMT3B-dependent de novo DNA methylation. These genes are then activated by lineage-specific promoter demethylation during distinct global Epigenetic Reprogramming events in migratory (~E8.5) and post-migratory (E10.5-11.5) PGCs. We propose that genes involved in genome defence are developmentally regulated primarily by promoter DNA methylation as a sensory mechanism that is coupled to the potential for TE activation during global 5mC erasure, thereby acting as a failsafe to ensure TE suppression and maintain genomic integrity in the germline.
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Parallel mechanisms of Epigenetic Reprogramming in the germline
Trends in genetics : TIG, 2012Co-Authors: Jamie A. Hackett, Jan J. Zylicz, M.a. SuraniAbstract:Germ cells possess the extraordinary and unique capacity to give rise to a new organism and create an enduring link between all generations. To acquire this property, primordial germ cells (PGCs) transit through an unprecedented programme of sequential Epigenetic events that culminates in an epigenomic basal state that is the foundation of totipotency. This process is underpinned by genome-wide DNA demethylation, which may occur through several overlapping pathways, including conversion to 5-hydroxymethylcytosine. We propose that the Epigenetic programme in PGCs operates through multiple parallel mechanisms to ensure robustness at the level of individual cells while also being flexible through functional redundancy to guarantee high fidelity of the process. Gaining a better understanding of the molecular mechanisms that direct Epigenetic Reprogramming in PGCs will enhance our ability to manipulate Epigenetic memory, cell-fate decisions and applications in regenerative medicine.
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Epigenetic Reprogramming of mouse germ cells toward totipotency.
Cold Spring Harbor symposia on quantitative biology, 2010Co-Authors: M.a. Surani, Petra HajkovaAbstract:Primordial germ cells (PGCs), the precursors of sperm and eggs, are the route to totipotency and require establishment of a unique epigenome in this lineage. The genetic program for PGC specification in the mouse also initiates Epigenetic Reprogramming that continues when PGCs migrate into the developing gonads. Among these later events is active and genome-wide DNA demethylation, which is linked to extensive chromatin remodeling. These extensive Epigenetic changes erase most, if not all, of the existing Epigenetic information, which resets the epigenome for totipotency. Recent evidence suggests that active DNA demethylation involves a base excision repair (BER) pathway. BER is mechanistically linked to DNA demethylation, but what triggers BER is currently under investigation. The methylated cytosine (5mC) could be modified by deamination or to 5hmC, which could induce BER. Detection of Tet1 expression specifically and coincidentally, at the time of BER in PGCs, suggests that conversion of 5mC to 5hmC might be involved, at least in part, during Epigenetic Reprogramming and DNA demethylation in germ cells.
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Self-renewing epiblast stem cells exhibit continual delineation of germ cells with Epigenetic Reprogramming in vitro
Development (Cambridge England), 2009Co-Authors: Katsuhiko Hayashi, M.a. SuraniAbstract:Pluripotent epiblast stem cells (EpiSCs) derived from postimplantation embryos exhibit properties that are characteristically different when compared with pluripotent embryonic stem cells (ESCs) derived from mouse blastocysts. However, EpiSCs are relatively less well characterised compared with ESCs. In particular, the relationship between EpiSCs and primordial germ cells (PGCs) is unknown, and is worthy of investigation because PGCs originate from postimplantation epiblast cells in vivo. We show that EpiSCs have an infinite capacity for generating PGCs, under conditions that sustain their pluripotency and self-renewal. These PGCs generated in vitro show appropriate transcriptional and Epigenetic Reprogramming events and are able to develop further into late germ cells. Notably, the PGCs can, in turn, be induced to undergo dedifferentiation into pluripotent embryonic germ cells (EGCs), which resemble ESCs and not the EpiSC from which they are derived. Our observations demonstrate intrinsic Reprogramming during specification of PGCs that results in the erasure of Epigenetic memory of EpiSCs following reactivation of the X-chromosome, DNA demethylation and re-expression of key pluripotency genes. This study provides novel insights into the nature and properties of EpiSCs, and introduces an in vitro model system that will be useful for investigations on PGC specification and on mechanisms regulating Epigenetic Reprogramming in germ cells.
Shunsuke Suzuki - One of the best experts on this subject based on the ideXlab platform.
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Postnatal Epigenetic Reprogramming in the germline of a marsupial, the tammar wallaby
Epigenetics & chromatin, 2013Co-Authors: Shunsuke Suzuki, Geoffrey Shaw, Marilyn B. RenfreeAbstract:Epigenetic Reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of Epigenetic Reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons. Demethylation of the H19 DMR was almost completed by 14 days postpartum and de-novo methylation started from 34 days postpartum. These stages correspond to 14 days after the completion of primordial germ cell migration into genital ridge (demethylation) and 9 days after the first detection of mitotic arrest (re-methylation) in the male germ cells. Interestingly, the PEG10 DMR was already unmethylated at 7 days postpartum, suggesting that the timing of Epigenetic Reprogramming is not the same at all genomic loci. Retrotransposon methylation was not completely removed after the demethylation event in the germ cells, similar to the situation in the mouse. Thus, despite the postnatal occurrence of Epigenetic Reprogramming and the persistence of genome-wide undermethylation for 20 days in the postnatal tammar, the relative timing and mechanism of germ cell Reprogramming are conserved between marsupials and eutherians. We suggest that the basic mechanism of Epigenetic Reprogramming had already been established before the marsupial-eutherian split and has been faithfully maintained for at least 160 million years and may reflect the timing of the onset of mitotic arrest in the male germline.
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postnatal Epigenetic Reprogramming in the germline of a marsupial the tammar wallaby
Epigenetics & Chromatin, 2013Co-Authors: Shunsuke Suzuki, Geoffrey Shaw, Marilyn B. RenfreeAbstract:Background Epigenetic Reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of Epigenetic Reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons.
Marilyn B. Renfree - One of the best experts on this subject based on the ideXlab platform.
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Postnatal Epigenetic Reprogramming in the germline of a marsupial, the tammar wallaby
Epigenetics & chromatin, 2013Co-Authors: Shunsuke Suzuki, Geoffrey Shaw, Marilyn B. RenfreeAbstract:Epigenetic Reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of Epigenetic Reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons. Demethylation of the H19 DMR was almost completed by 14 days postpartum and de-novo methylation started from 34 days postpartum. These stages correspond to 14 days after the completion of primordial germ cell migration into genital ridge (demethylation) and 9 days after the first detection of mitotic arrest (re-methylation) in the male germ cells. Interestingly, the PEG10 DMR was already unmethylated at 7 days postpartum, suggesting that the timing of Epigenetic Reprogramming is not the same at all genomic loci. Retrotransposon methylation was not completely removed after the demethylation event in the germ cells, similar to the situation in the mouse. Thus, despite the postnatal occurrence of Epigenetic Reprogramming and the persistence of genome-wide undermethylation for 20 days in the postnatal tammar, the relative timing and mechanism of germ cell Reprogramming are conserved between marsupials and eutherians. We suggest that the basic mechanism of Epigenetic Reprogramming had already been established before the marsupial-eutherian split and has been faithfully maintained for at least 160 million years and may reflect the timing of the onset of mitotic arrest in the male germline.
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postnatal Epigenetic Reprogramming in the germline of a marsupial the tammar wallaby
Epigenetics & Chromatin, 2013Co-Authors: Shunsuke Suzuki, Geoffrey Shaw, Marilyn B. RenfreeAbstract:Background Epigenetic Reprogramming is essential to restore totipotency and to reset genomic imprints during mammalian germ cell development and gamete formation. The dynamic DNA methylation change at DMRs (differentially methylated regions) within imprinted domains and of retrotransposons is characteristic of this process. Both marsupials and eutherian mammals have genomic imprinting but these two subgroups have been evolving separately for up to 160 million years. Marsupials have a unique reproductive strategy and deliver tiny, altricial young that complete their development within their mother's pouch. Germ cell proliferation in the genital ridge continues after birth in the tammar wallaby (Macropus eugenii), and it is only after 25 days postpartum that female germ cells begin to enter meiosis and male germ cells begin to enter mitotic arrest. At least two marsupial imprinted loci (PEG10 and H19) also have DMRs. To investigate the evolution of Epigenetic Reprogramming in the marsupial germline, here we collected germ cells from male pouch young of the tammar wallaby and analysed the methylation status of PEG10 and H19 DMR, an LTR (long terminal repeat) and a non-LTR retrotransposons.
Petra Hajkova - One of the best experts on this subject based on the ideXlab platform.
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Dynamic changes in H1 subtype composition during Epigenetic Reprogramming.
The Journal of cell biology, 2017Co-Authors: Annalisa Izzo, Petra Hajkova, Céline Ziegler-birling, Peter W. S. Hill, Lydia Brondani, Maria-elena Torres-padilla, Robert SchneiderAbstract:In mammals, histone H1 consists of a family of related proteins, including five replication-dependent (H1.1-H1.5) and two replication-independent (H1.10 and H1.0) subtypes, all expressed in somatic cells. To systematically study the expression and function of H1 subtypes, we generated knockin mouse lines in which endogenous H1 subtypes are tagged. We focused on key developmental periods when Epigenetic Reprogramming occurs: early mouse embryos and primordial germ cell development. We found that dynamic changes in H1 subtype expression and localization are tightly linked with chromatin remodeling and might be crucial for transitions in chromatin structure during Reprogramming. Although all somatic H1 subtypes are present in the blastocyst, each stage of preimplantation development is characterized by a different combination of H1 subtypes. Similarly, the relative abundance of somatic H1 subtypes can distinguish male and female chromatin upon sex differentiation in developing germ cells. Overall, our data provide new insights into the chromatin changes underlying Epigenetic Reprogramming. We suggest that distinct H1 subtypes may mediate the extensive chromatin remodeling occurring during Epigenetic Reprogramming and that they may be key players in the acquisition of cellular totipotency and the establishment of specific cellular states.
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DNA demethylation, Tet proteins and 5-hydroxymethylcytosine in Epigenetic Reprogramming: an emerging complex story.
Genomics, 2014Co-Authors: Peter W. S. Hill, Rachel Amouroux, Petra HajkovaAbstract:Epigenetic Reprogramming involves processes that lead to the erasure of Epigenetic information, reverting the chromatin template to a less differentiated state. Extensive Epigenetic Reprogramming occurs both naturally during mammalian development in the early embryo and the developing germ line, and artificially in various in vitro Reprogramming systems. Global DNA demethylation appears to be a shared attribute of Reprogramming events, and understanding DNA methylation dynamics is thus of considerable interest. Recently, the Tet enzymes, which catalyse the iterative oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, 5-formylcytosine and 5-carboxylcytosine, have emerged as potential drivers of Epigenetic Reprogramming. Although some of the recent studies point towards the direct role of Tet proteins in the removal of DNA methylation, the accumulating evidence suggests that the processes underlying DNA methylation dynamics might be more complex. Here, we review the current evidence, highlighting the agreements and the discrepancies between the suggested models and the experimental evidence.
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Epigenetic Reprogramming in the germline: towards the ground state of the epigenome
Philosophical transactions of the Royal Society of London. Series B Biological sciences, 2011Co-Authors: Petra HajkovaAbstract:Epigenetic Reprogramming in the germline provides a developmental model to study the erasure of Epigenetic memory as it occurs naturally in vivo in the course of normal embryonic development. Our data show that germline Reprogramming comprises both active DNA demethylation and extensive chromatin remodelling that are mechanistically linked through the activation of the base excision DNA repair pathway involved in the DNA demethylation process. The observed molecular hallmarks of the germline Reprogramming exhibit intriguing similarities to other dedifferentiation or regeneration systems, pointing towards the existence of unifying molecular pathways underlying cell fate reversal. Elucidation of molecular processes involved in the resetting of Epigenetic information in vivo will thus add to our ability to manipulate cell fate and to restore pluripotency in in vitro settings.
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Epigenetic Reprogramming--taking a lesson from the embryo.
Current opinion in cell biology, 2010Co-Authors: Petra HajkovaAbstract:Epigenetic Reprogramming involves processes that lead to the erasure of Epigenetic information. Such instances are typically connected with the reversal of differentiation and can potentially lead to the re-establishment of the pluripotent (embryonic stem (ES)-like) phenotype. Genome-wide Epigenetic Reprogramming occurs naturally in vivo in the course of normal mammalian development. Although in vitro Reprogramming systems that can restore pluripotency in somatic cell have been designed, they are still very inefficient and the process requires considerably more time than the Reprogramming processes that occur in vivo. Careful analysis of the developmental Reprogramming events can give us mechanistic clues and enable us to design better in vitro experimental strategies.
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Epigenetic Reprogramming of mouse germ cells toward totipotency.
Cold Spring Harbor symposia on quantitative biology, 2010Co-Authors: M.a. Surani, Petra HajkovaAbstract:Primordial germ cells (PGCs), the precursors of sperm and eggs, are the route to totipotency and require establishment of a unique epigenome in this lineage. The genetic program for PGC specification in the mouse also initiates Epigenetic Reprogramming that continues when PGCs migrate into the developing gonads. Among these later events is active and genome-wide DNA demethylation, which is linked to extensive chromatin remodeling. These extensive Epigenetic changes erase most, if not all, of the existing Epigenetic information, which resets the epigenome for totipotency. Recent evidence suggests that active DNA demethylation involves a base excision repair (BER) pathway. BER is mechanistically linked to DNA demethylation, but what triggers BER is currently under investigation. The methylated cytosine (5mC) could be modified by deamination or to 5hmC, which could induce BER. Detection of Tet1 expression specifically and coincidentally, at the time of BER in PGCs, suggests that conversion of 5mC to 5hmC might be involved, at least in part, during Epigenetic Reprogramming and DNA demethylation in germ cells.