Maternal H3K27me3 controls DNA methylation-independent imprinting

Inoue, Atsuyuki; Jiang, Lan; Lu, Falong; Suzuki, Takahiro; Zhang, Yi

doi:10.1038/nature23262

Cited by 365 publications

(446 citation statements)

References 53 publications

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“…Interestingly, the knockdown of KDM6B in SCNT embryos leads to a moderate increase in the expression of KDM6A, consistent with our previous findings in mouse parthenogenetic embryos [41]. While our paper was under preparation, another study reported the identification of H3K27me3-dependent imprinting genes (which include Gab1, Sfmbt2, and Slc38a4), and previous studies have shown that these genes exhibit a loss of imprinting in SCNT embryos [57,58]. This provides an explanation for why the knockdown of the H3K27me3 demethylase KDM6B promotes SCNT efficiency.…”

Section: Discussionsupporting

confidence: 91%

KDM 6A and KDM 6B play contrasting roles in nuclear transfer embryos revealed by MERVL reporter system

et al. 2018

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Despite the success of animal cloning by somatic cell nuclear transfer (SCNT) in many species, the method is limited by its low efficiency. After zygotic genome activation (ZGA) during mouse development, a large number of endogenous retroviruses (ERVs) are expressed, including the murine endogenous retrovirus‐L (MuERVL/MERVL). In this study, we generate a series of MERVL reporter mouse strains to detect the ZGA event in embryos. We show that the majority of SCNT embryos do not undergo ZGA, and H3K27me3 prevents SCNT reprogramming. Overexpression of the H3K27me3‐specific demethylase KDM6A, but not of KDM6B, improves the efficiency of SCNT. Conversely, knockdown of KDM6B not only facilitates ZGA, but also impedes ectopic Xist expression in SCNT reprogramming. Furthermore, knockdown of KDM6B increases the rate of SCNT‐derived embryonic stem cells from Duchenne muscular dystrophy embryos. These results not only provide insight into the mechanisms underlying failures of SCNT, but also may extend the applications of SCNT.

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Section: Discussionsupporting

confidence: 91%

KDM 6A and KDM 6B play contrasting roles in nuclear transfer embryos revealed by MERVL reporter system

et al. 2018

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“…This complex is recruited to and silences specific regions of the genome by transferring methyl groups onto lysine 27 of histone H3. This chromatin modification has well-defined roles in the maintenance of the stem cell state and genomic imprinting (Juan et al, 2016; Inoue et al, 2017). Collectively, these observations indicate that oxygen concentrations have a strong influence on the control of chromatin modifying enzymes and significantly impact the regulation of two crucial pluripotency-associated genes.…”

Section: Discussionmentioning

confidence: 99%

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

Skiles

Kester

Pryor

et al. 2018

Gene Expression Patterns

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Embryo culture and assisted reproductive technologies have been associated with a disproportionately high number of epigenetic abnormalities in the resulting offspring. However, the mechanisms by which these techniques influence the epigenome remain poorly defined. In this study, we evaluated the capacity of oxygen concentration to influence the transcriptional control of a selection of key enzymes regulating chromatin structure. In mouse embryonic stem cells, oxygen concentrations modulated the transcriptional regulation of the TET family of enzymes, as well as the de novo methyltransferase Dnmt3a. These transcriptional changes were associated with alterations in the control of multiple imprinted genes, including H19, Igf2, Igf2r, and Peg3. Similarly, exposure of in vitro produced bovine embryos to atmospheric oxygen concentrations was associated with disruptions in the transcriptional regulation of TET1, TET3, and DNMT3a, along with the DNA methyltransferase co-factor HELLS. In addition, exposure to high oxygen was associated with alterations in the abundance of transcripts encoding members of the Polycomb repressor complex (EED and EZH2), the histone methyltransferase SETDB1 and multiple histone demethylases (KDM1A, KDM4B, and KDM4C). These disruptions were accompanied by a reduction in embryo viability and suppression of the pluripotency genes NANOG and SOX2. These experiments demonstrate that oxygen has the capacity to modulate the transcriptional control of chromatin modifying genes involved in the establishment and maintenance of both pluripotency and genomic imprinting.

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“…The regulation of chromatin structure in germ cells is pivotal as these cells are the bridge between generations and therefore potential vector of epigenetic information. In particular, H3K27me3 has been shown to be involved in parental imprinting 21,22,23 . Yet, in contrast to the extensive characterization of PRC2 in models such as mouse embryonic stem cells (ESC), much less is known about the regulation of its enzymatic activity in germ cells.…”

Section: Theirmentioning

confidence: 99%

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

Ragazzini

Pérez-Palacios

Baymaz

et al. 2019

Preprint

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The Polycomb machinery is required for the proper orchestration of gene expression by virtue of its critical role in maintaining transcriptional silencing. It is composed of several chromatin modifying complexes, including Polycomb Repressive Complex 2 (PRC2), which deposits H3K27me2/3. Here, we report the identification of a new cofactor of PRC2, EZHIP (EZH1/2 Inhibitory Protein), expressed predominantly in the gonads. EZHIP limits the enzymatic activity of PRC2 and lessens the interaction between the core complex and its accessory subunits, but does not interfere with PRC2 recruitment to chromatin. Deletion of Ezhip leads to a global increase in H3K27me2/3 deposition both during spermatogenesis and at late stages of oocyte maturation. This alteration of the epigenetic content of mature oocytes does not affect the initial number of follicles but is associated with a reduction of follicles in aging mice. We provide evidences that mature oocytes Ezhip -/-are not fully functional and that fertility is strongly impaired in Ezhip -/-females. Altogether, our study uncovers EZHIP as a novel functional player in the comprehensive chromatin remodeling that occurs in the gonads.

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Maternal H3K27me3 controls DNA methylation-independent imprinting

Cited by 365 publications

References 53 publications

KDM 6A and KDM 6B play contrasting roles in nuclear transfer embryos revealed by MERVL reporter system

KDM 6A and KDM 6B play contrasting roles in nuclear transfer embryos revealed by MERVL reporter system

Oxygen-induced alterations in the expression of chromatin modifying enzymes and the transcriptional regulation of imprinted genes

EZHIP constrains Polycomb Repressive Complex 2 activity in germ cells

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