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      PRMT5 Protects Genomic Integrity during Global DNA Demethylation in Primordial Germ Cells and Preimplantation Embryos

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          Summary

          Primordial germ cells (PGCs) and preimplantation embryos undergo epigenetic reprogramming, which includes comprehensive DNA demethylation. We found that PRMT5, an arginine methyltransferase, translocates from the cytoplasm to the nucleus during this process. Here we show that conditional loss of PRMT5 in early PGCs causes complete male and female sterility, preceded by the upregulation of LINE1 and IAP transposons as well as activation of a DNA damage response. Similarly, loss of maternal-zygotic PRMT5 also leads to IAP upregulation. PRMT5 is necessary for the repressive H2A/H4R3me2s chromatin modification on LINE1 and IAP transposons in PGCs, directly implicating this modification in transposon silencing during DNA hypomethylation. PRMT5 translocates back to the cytoplasm subsequently, to participate in the previously described PIWI-interacting RNA (piRNA) pathway that promotes transposon silencing via de novo DNA remethylation. Thus, PRMT5 is directly involved in genome defense during preimplantation development and in PGCs at the time of global DNA demethylation.

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          Highlights

          • PRMT5 is essential for primordial germ cell (PGC) development

          • PRMT5 translocates to the nucleus of PGCs during epigenetic reprogramming

          • PRMT5-dependent H2A/H4R3me2s is enriched on transposable elements in PGCs

          • PRMT5 loss in PGCs or preimplantation embryos activates transposable elements

          Abstract

          Primordial germ cells undergo epigenetic reprogramming that involves DNA demethylation, yet repressed elements such as transposons are not activated. Kim et al. show that Prmt5 is essential in the suppression of transposable elements during epigenetic reprogramming in primordial germ cells and is crucial for their development.

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          Most cited references39

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          MIWI2 is essential for spermatogenesis and repression of transposons in the mouse male germline.

          Small RNAs associate with Argonaute proteins and serve as sequence-specific guides for regulation of mRNA stability, productive translation, chromatin organization, and genome structure. In animals, the Argonaute superfamily segregates into two clades. The Argonaute clade acts in RNAi and in microRNA-mediated gene regulation in partnership with 21-22 nt RNAs. The Piwi clade, and their 26-30 nt piRNA partners, have yet to be assigned definitive functions. In mice, two Piwi-family members have been demonstrated to have essential roles in spermatogenesis. Here, we examine the effects of disrupting the gene encoding the third family member, MIWI2. Miwi2-deficient mice display a meiotic-progression defect in early prophase of meiosis I and a marked and progressive loss of germ cells with age. These phenotypes may be linked to an inappropriate activation of transposable elements detected in Miwi2 mutants. Our observations suggest a conserved function for Piwi-clade proteins in the control of transposons in the germline.
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            Blimp1 is a critical determinant of the germ cell lineage in mice.

            Germ cell fate in mice is induced in pluripotent epiblast cells in response to signals from extraembryonic tissues. The specification of approximately 40 founder primordial germ cells and their segregation from somatic neighbours are important events in early development. We have proposed that a critical event during this specification includes repression of a somatic programme that is adopted by neighbouring cells. Here we show that Blimp1 (also known as Prdm1), a known transcriptional repressor, has a critical role in the foundation of the mouse germ cell lineage, as its disruption causes a block early in the process of primordial germ cell formation. Blimp1-deficient mutant embryos form a tight cluster of about 20 primordial germ cell-like cells, which fail to show the characteristic migration, proliferation and consistent repression of homeobox genes that normally accompany specification of primordial germ cells. Furthermore, our genetic lineage-tracing experiments indicate that the Blimp1-positive cells originating from the proximal posterior epiblast cells are indeed the lineage-restricted primordial germ cell precursors.
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              Epigenetic reprogramming in mouse primordial germ cells.

              Genome-wide epigenetic reprogramming in mammalian germ cells, zygote and early embryos, plays a crucial role in regulating genome functions at critical stages of development. We show here that mouse primordial germ cells (PGCs) exhibit dynamic changes in epigenetic modifications between days 10.5 and 12.5 post coitum (dpc). First, contrary to previous suggestions, we show that PGCs do indeed acquire genome-wide de novo methylation during early development and migration into the genital ridge. However, following their entry into the genital ridge, there is rapid erasure of DNA methylation of regions within imprinted and non-imprinted loci. For most genes, the erasure commences simultaneously in PGCs in both male and female embryos, which is completed within 1 day of development. Based on the kinetics of this process, we suggest that this is an active demethylation process initiated upon the entry of PGCs into the gonadal anlagen. The timing of reprogramming in PGCs is crucial since it ensures that germ cells of both sexes acquire an equivalent epigenetic state prior to the differentiation of the definitive male and female germ cells in which new parental imprints are established subsequently. Some repetitive elements, however, show incomplete erasure, which may be essential for chromosome stability and for preventing activation of transposons to reduce the risk of germline mutations. Aberrant epigenetic reprogramming in the germ line would cause the inheritance of epimutations that may have consequences for human diseases as suggested by studies on mouse models. Copyright 2002 Elsevier Science Ireland Ltd.
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                Author and article information

                Contributors
                Journal
                Mol Cell
                Mol. Cell
                Molecular Cell
                Cell Press
                1097-2765
                1097-4164
                20 November 2014
                20 November 2014
                : 56
                : 4
                : 564-579
                Affiliations
                [1 ]Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK
                [2 ]Department of Physiology, Development, and Neuroscience, University of Cambridge, Downing Street, Cambridge CB2 3DY, UK
                [3 ]Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK
                [4 ]College of Life Science, Inner Mongolia University, No. 235 Da Xue Xi Road, Huhhot, Inner Mongolia 010021, China
                Author notes
                []Corresponding author a.surani@ 123456gurdon.cam.ac.uk
                Article
                S1097-2765(14)00787-4
                10.1016/j.molcel.2014.10.003
                4250265
                25457166
                f860cbaa-29d4-4021-b9e2-5e046ad12f58
                © 2014 Elsevier Inc. All rights reserved.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

                History
                : 30 May 2014
                : 3 September 2014
                : 2 October 2014
                Categories
                Article

                Molecular biology
                Molecular biology

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