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1.
Yuka Tamura Tatsuya Ohhata Hiroyuki Niida Satoshi Sakai Chiharu Uchida Kazuma Masumoto Fuminori Katou Anton Wutz Masatoshi Kitagawa 《EMBO reports》2021,22(9)
The reactivation of X‐linked genes is observed in some primary breast tumors. Two active X chromosomes are also observed in female embryonic stem cells (ESCs), but whether double doses of X‐linked genes affect DNA repair efficiency remains unclear. Here, we establish isogenic female/male ESCs and show that the female ESCs are more sensitive to camptothecin and have lower gene targeting efficiency than male ESCs, suggesting that homologous recombination (HR) efficiency is reduced in female ESCs. We also generate Xist‐inducible female ESCs and show that the lower HR efficiency is restored when X chromosome inactivation is induced. Finally, we assess the X‐linked genes with a role in DNA repair and find that Brcc3 is one of the genes involved in a network promoting proper HR. Our findings link the double doses of X‐linked genes with lower DNA repair activity, and this may have relevance for common diseases in female patients, such as breast cancer. 相似文献
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X-chromosome inactivation is an epigenetic hallmark of mammalian development. Chromosome-wide regulation of the X-chromosome
is essential in embryonic and germ cell development. In the male germline, the X-chromosome goes through meiotic sex chromosome
inactivation, and the chromosome-wide silencing is maintained from meiosis into spermatids before the transmission to female
embryos. In early female mouse embryos, X-inactivation is imprinted to occur on the paternal X-chromosome, representing the
epigenetic programs acquired in both parental germlines. Recent advances revealed that the inactive X-chromosome in both females
and males can be dissected into two elements: repeat elements versus unique coding genes. The inactive paternal X in female
preimplantation embryos is reactivated in the inner cell mass of blastocysts in order to subsequently allow the random form
of X-inactivation in the female embryo, by which both Xs have an equal chance of being inactivated. X-chromosome reactivation
is regulated by pluripotency factors and also occurs in early female germ cells and in pluripotent stem cells, where X-reactivation
is a stringent marker of naive ground state pluripotency. Here we summarize recent progress in the study of X-inactivation
and X-reactivation during mammalian reproduction and development as well as in pluripotent stem cells. 相似文献
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Bone morphogenetic protein and retinoic acid synergistically specify female germ‐cell fate in mice
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Hidetaka Miyauchi Hiroshi Ohta So Nagaoka Fumio Nakaki Kotaro Sasaki Katsuhiko Hayashi Yukihiro Yabuta Tomonori Nakamura Takuya Yamamoto Mitinori Saitou 《The EMBO journal》2017,36(21):3100-3119
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Early loss of Xist RNA expression and inactive X chromosome associated chromatin modification in developing primordial germ cells 总被引:1,自引:0,他引:1
BACKGROUND: The inactive X chromosome characteristic of female somatic lineages is reactivated during development of the female germ cell lineage. In mouse, analysis of protein products of X-linked genes and/or transgenes located on the X chromosome has indicated that reactivation occurs after primordial germ cells reach the genital ridges. PRINCIPAL FINDINGS/METHODOLOGY: We present evidence that the epigenetic reprogramming of the inactive X-chromosome is initiated earlier than was previously thought, around the time that primordial germ cells (PGCs) migrate through the hindgut. Specifically, we find that Xist RNA expression, the primary signal for establishment of chromosome silencing, is extinguished in migrating PGCs. This is accompanied by displacement of Polycomb-group repressor proteins Eed and Suz(12), and loss of the inactive X associated histone modification, methylation of histone H3 lysine 27. CONCLUSIONS/SIGNIFICANCE: We conclude that X reactivation in primordial germ cells occurs progressively, initiated by extinction of Xist RNA around the time that germ cells migrate through the hindgut to the genital ridges. The events that we observe are reminiscent of X reactivation of the paternal X chromosome in inner cell mass cells of mouse pre-implantation embryos and suggest a unified model in which execution of the pluripotency program represses Xist RNA thereby triggering progressive reversal of epigenetic silencing of the X chromosome. 相似文献
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The immune system plays a major role in the protection against cancer. Identifying and characterizing the pathways mediating this immune surveillance are thus critical for understanding how cancer cells are recognized and eliminated. Aneuploidy is a hallmark of cancer, and we previously found that untransformed cells that had undergone senescence due to highly abnormal karyotypes are eliminated by natural killer (NK) cells in vitro. However, the mechanisms underlying this process remained elusive. Here, using an in vitro NK cell killing system, we show that non‐cell‐autonomous mechanisms in aneuploid cells predominantly mediate their clearance by NK cells. Our data indicate that in untransformed aneuploid cells, NF‐κB signaling upregulation is central to elicit this immune response. Inactivating NF‐κB abolishes NK cell‐mediated clearance of untransformed aneuploid cells. In cancer cell lines, NF‐κB upregulation also correlates with the degree of aneuploidy. However, such upregulation in cancer cells is not sufficient to trigger NK cell‐mediated clearance, suggesting that additional mechanisms might be at play during cancer evolution to counteract NF‐κB‐mediated immunogenicity. 相似文献
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Jingru Tian Dingyao Zhang Vadim Kurbatov Qinrong Wang Yadong Wang Dorthy Fang Lizhen Wu Marcus Bosenberg Mandar D Muzumdar Sajid Khan Qianjin Lu Qin Yan Jun Lu 《The EMBO journal》2021,40(7)
5‐Fluorouracil (5‐FU) is a widely used chemotherapeutic drug, but the mechanisms underlying 5‐FU efficacy in immunocompetent hosts in vivo remain largely elusive. Through modeling 5‐FU response of murine colon and melanoma tumors, we report that effective reduction of tumor burden by 5‐FU is dependent on anti‐tumor immunity triggered by the activation of cancer‐cell‐intrinsic STING. While the loss of STING does not induce 5‐FU resistance in vitro, effective 5‐FU responsiveness in vivo requires cancer‐cell‐intrinsic cGAS, STING, and subsequent type I interferon (IFN) production, as well as IFN‐sensing by bone‐marrow‐derived cells. In the absence of cancer‐cell‐intrinsic STING, a much higher dose of 5‐FU is needed to reduce tumor burden. 5‐FU treatment leads to increased intratumoral T cells, and T‐cell depletion significantly reduces the efficacy of 5‐FU in vivo. In human colorectal specimens, higher STING expression is associated with better survival and responsiveness to chemotherapy. Our results support a model in which 5‐FU triggers cancer‐cell‐initiated anti‐tumor immunity to reduce tumor burden, and our findings could be harnessed to improve therapeutic effectiveness and toxicity for colon and other cancers. 相似文献
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Yan Yuan Quan Zhou Haifeng Wan Bin Shen Xuepeng Wang Mei Wang Chunjing Feng Mingming Xie Tiantian Gu Tao Zhou Rui Fu Xingxu Huang Qi Zhou Jiahao Sha Xiao-Yang Zhao 《Cell research》2015,25(7):851-863
Genetic mutations could cause sperm deficiency, leading to male infertility. Without functional gametes in the testes, patients cannot produce progeny even with assisted reproduction technologies such as in vitro fertilization. It has been a major challenge to restore the fertility of gamete-deficient patients due to genetic mutations. In this study, using a Kitw/Kitwv mouse model, we investigated the feasibility of generating functional sperms from gamete-deficient mice by combining the reprogramming and gene correcting technologies. We derived embryonic stem cells from cloned embryos (ntESCs) that were created by nuclear transfer of Kitw/Kitwv somatic cells. Then we generated gene-corrected ntESCs using TALEN-mediated gene editing. The repaired ntESCs could further differentiate into primordial germ cell-like cells (PGCLCs) in vitro. RFP-labeled PGCLCs from the repaired ntESCs could produce functional sperms in mouse testes. In addition, by co-transplantation with EGFP-labeled testis somatic cells into the testes where spermatogenesis has been chemically damaged or by transplantation into Kitw/Kitwv infertile testes, non-labeled PGCLCs could also produce haploid gametes, supporting full-term mouse development. Our study explores a new path to rescue male infertility caused by genetic mutations. 相似文献
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Gillich A Bao S Grabole N Hayashi K Trotter MW Pasque V Magnúsdóttir E Surani MA 《Cell Stem Cell》2012,10(4):425-439
Epigenetic reprogramming in early germ cells is critical toward the establishment of totipotency, but investigations of the germline events are intractable. An objective cell culture-based system could provide mechanistic insight on how the key determinants of primordial germ cells (PGCs), including Prdm14, induce reprogramming in germ cells to an epigenetic ground state. Here we show a Prdm14-Klf2 synergistic effect that can accelerate and enhance reversion of mouse epiblast stem cells (epiSCs) to a naive pluripotent state, including X reactivation and DNA demethylation. Notably, Prdm14 alone has little effect on epiSC reversion, but it enhances the competence for reprogramming and potentially PGC specification. Reprogramming of epiSCs by the combinatorial effect of Prdm14-Klf2 involves key epigenetic changes, which might have an analogous role in PGCs. Our study provides a paradigm toward a systematic analysis of how other key genes contribute to complex and dynamic events of reprogramming in the germline. 相似文献
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Chuva de Sousa Lopes SM Hayashi K Shovlin TC Mifsud W Surani MA McLaren A 《PLoS genetics》2008,4(2):e30
In the early epiblast of female mice, one of the two X chromosomes is randomly inactivated by a Xist-dependent mechanism, involving the recruitment of Ezh2-Eed and the subsequent trimethylation of histone 3 on lysine 27 (H3K27me3). We demonstrate that this random inactivation process applies also to the primordial germ cell (PGC) precursors, located in the proximal region of the epiblast. PGC specification occurs at about embryonic day (E)7.5, in the extraembryonic mesoderm, after which the germ cells enter the endoderm of the invaginating hindgut. As they migrate towards the site of the future gonads, the XX PGCs gradually lose the H3K27me3 accumulation on the silent X chromosome. However, using a GFP transgene inserted into the X chromosome, we observed that the XX gonadal environment (independently of the gender) is important for the substantial reactivation of the inactive X chromosome between E11.5 and E13.5, but is not required for X-chromosome reactivation during the derivation of pluripotent embryonic germ cells. We describe in detail one of the key events during female PGC development, the epigenetic reprogramming of the X chromosome, and demonstrate the role of the XX somatic genital ridge in this process. 相似文献
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The pairing of sex chromosomes during meiosis in male mammals is associated with ongoing heterochromatinization and X inactivation. This process occurs in a specific area of the nucleus that can be discerned morphologically: the sex vesicle or XY-body. In contrast to X inactivation in the somatic cells of female mammals the reasons for X inactivation in the male germline remain obscure. We have recently demonstrated that the inactive X chromosome in somatic cells of female mammals is marked by a high concentration of histone macroH2A. Here we investigate X inactivation in the meiotic cells of the male germline. We demonstrate here that macroH2A1.2 is present in the nuclei of germ cells starting first with localization that is largely, if not exclusively, to the developing XY-body in early pachytene spermatocytes. Our results suggest that inactivation of sex chromosomes in the male germ cell includes a major alteration of the nucleosomal structure. 相似文献
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Anna Kouznetsova Jian Guo Liu Sonata Valentiniene Hjalmar Brismar Christer Hg 《Aging cell》2022,21(7)
Ageing severely affects the chromosome segregation process in human oocytes resulting in aneuploidy, infertility and developmental disorders. A considerable amount of segregation errors in humans are introduced at the second meiotic division. We have here compared the chromosome segregation process in young adult and aged female mice during the second meiotic division. More than half of the oocytes in aged mice displayed chromosome segregation irregularities at anaphase II, resulting in dramatically increased level of aneuploidy in haploid gametes, from 4% in young adult mice to 30% in aged mice. We find that the post‐metaphase II process that efficiently corrects aberrant kinetochore‐microtubule attachments in oocytes in young adult mice is approximately 10‐fold less efficient in aged mice, in particular affecting chromosomes that show small inter‐centromere distances at the metaphase II stage in aged mice. Our results reveal that post‐metaphase II processes have critical impact on age‐dependent aneuploidy in mammalian eggs. 相似文献
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Melanie Issigonis Akshada B. Redkar Tania Rozario Umair W. Khan Rosa Mejia-Sanchez Sylvain W. Lapan Peter W. Reddien Phillip A. Newmark 《PLoS biology》2022,20(7)
Sexually reproducing animals segregate their germline from their soma. In addition to gamete-producing gonads, planarian and parasitic flatworm reproduction relies on yolk cell–generating accessory reproductive organs (vitellaria) supporting development of yolkless oocytes. Despite the importance of vitellaria for flatworm reproduction (and parasite transmission), little is known about this unique evolutionary innovation. Here, we examine reproductive system development in the planarian Schmidtea mediterranea, in which pluripotent stem cells generate both somatic and germ cell lineages. We show that a homolog of the pluripotency factor Klf4 is expressed in primordial germ cells (PGCs), presumptive germline stem cells (GSCs), and yolk cell progenitors. Knockdown of this klf4-like (klf4l) gene results in animals that fail to specify or maintain germ cells; surprisingly, they also fail to maintain yolk cells. We find that yolk cells display germ cell–like attributes and that vitellaria are structurally analogous to gonads. In addition to identifying a new proliferative cell population in planarians (yolk cell progenitors) and defining its niche, our work provides evidence supporting the hypothesis that flatworm germ cells and yolk cells share a common evolutionary origin. 相似文献
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Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers
Stefanie Seisenberger Julian R. Peat Timothy A. Hore Fátima Santos Wendy Dean Wolf Reik 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2013,368(1609)
In mammalian development, epigenetic modifications, including DNA methylation patterns, play a crucial role in defining cell fate but also represent epigenetic barriers that restrict developmental potential. At two points in the life cycle, DNA methylation marks are reprogrammed on a global scale, concomitant with restoration of developmental potency. DNA methylation patterns are subsequently re-established with the commitment towards a distinct cell fate. This reprogramming of DNA methylation takes place firstly on fertilization in the zygote, and secondly in primordial germ cells (PGCs), which are the direct progenitors of sperm or oocyte. In each reprogramming window, a unique set of mechanisms regulates DNA methylation erasure and re-establishment. Recent advances have uncovered roles for the TET3 hydroxylase and passive demethylation, together with base excision repair (BER) and the elongator complex, in methylation erasure from the zygote. Deamination by AID, BER and passive demethylation have been implicated in reprogramming in PGCs, but the process in its entirety is still poorly understood. In this review, we discuss the dynamics of DNA methylation reprogramming in PGCs and the zygote, the mechanisms involved and the biological significance of these events. Advances in our understanding of such natural epigenetic reprogramming are beginning to aid enhancement of experimental reprogramming in which the role of potential mechanisms can be investigated in vitro. Conversely, insights into in vitro reprogramming techniques may aid our understanding of epigenetic reprogramming in the germline and supply important clues in reprogramming for therapies in regenerative medicine. 相似文献
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Pedro M O Ventura Milica Gakovic Berenice A Fischer Laura Spinelli Giorgia Rota Shalini Pathak Hanif J Khameneh Alessandro Zenobi Sarah Thomson Walter Birchmeier Doreen A Cantrell Greta Guarda 《EMBO reports》2022,23(11)
Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as PD‐1. Blockade of PD‐1 leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase PTPN11 (known as SHP‐2) is essential for PD‐1 signaling in T cells, suggesting functional redundancy with the homologous phosphatase PTPN6 (SHP‐1). Therefore, we investigated the effect of concomitant Ptpn6 and Ptpn11 deletion in T cells on their ability to mount antitumour responses. In vivo data show that neither sustained nor acute Ptpn6/11 deletion improves T cell‐mediated tumor control. Sustained loss of Ptpn6/11 also impairs the therapeutic effects of anti‐PD1 treatment. In vitro results show that Ptpn6/11‐deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analyses reveal substantial alterations, including in apoptosis‐related pathways. These data indicate that concomitant ablation of Ptpn6/11 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches. 相似文献