Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways

Jullien, Jérôme; Vodnala, Munender; Pasque, Vincent; Oikawa, Mami; Miyamoto, Kazuaki; Allen, George E.; David, Sarah-Anne; Brochard, Vincent; Wang, Stan; Bradshaw, Charles R.; Koseki, Haruhiko; Sartorelli, Vittorio; Beaujean, Nathalie; Gurdon, J. B.

doi:10.1016/j.molcel.2017.01.030

Cited by 41 publications

(38 citation statements)

References 48 publications

(78 reference statements)

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“…H3K27me3 is a repressive chromatin mark, and its erasure by KDM6B increased the average expression level of resistance genes during SCNT reprogramming in Xenopus, although there was no indication that KDM6B overexpression affected the efficiency of SCNT reprogramming (48). Another study showed that KDM6A directly interacts with the reprogramming factors Octamer-binding transcription factor 4 (sex determining region Y)-box 2 and Krüppel-like factor 4 to facilitate induced pluripotent stem cell generation, and that the absence of KDM6A constituted a major barrier for the re-establishment of pluripotency (49).…”

Section: Discussionmentioning

confidence: 97%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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Aberrant epigenetic reprogramming is a major factor of developmental failure of cloned embryos. Histone H3 lysine 27 trimethylation (H3K27me3), a histone mark for transcriptional repression, plays important roles in mammalian embryonic development and induced pluripotent stem cell (iPSC) generation. The global loss of H3K27me3 marks may facilitate iPSC generation in mice and humans. However, the H3K27me3 level and its role in bovine somatic cell nuclear transfer (SCNT) reprogramming remain poorly understood. Here, we show that SCNT embryos exhibit global H3K27me3 hypermethylation from the 2‐ to 8‐cell stage and that its removal by ectopically expressed H3K27me3 lysine demethylase (KDM)6A greatly improves nuclear reprogramming efficiency. In contrast, H3K27me3 reduction by H3K27me3 methylase enhancer of zeste 2 polycomb repressive complex knockdown or donor cell treatment with the enhancer of zeste 2 polycomb repressive complex—selective inhibitor GSK343 suppressed blastocyst formation by SCNT embryos. KDM6A overexpression enhanced the transcription of genes involved in cell adhesion and cellular metabolism and X‐linked genes. Furthermore, we identified methyl‐CpG‐binding domain protein 3‐like 2, which was reactivated by KDM6A, as a factor that is required for effective reprogramming in bovines. These results show that H3K27me3 functions as an epigenetic barrier and that KDM6A overexpression improves SCNT efficiency by facilitating transcriptional reprogramming.—Zhou, C., Wang, Y., Zhang, J., Su, J., An, Q., Liu, X., Zhang, M., Wang, Y., Liu, J., Zhang, Y. H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency. FASEB J. 33, 4638–4652 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 97%

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

et al. 2019

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“…These studies demonstrated that differentially expressed states can be transmitted across cell divisions, once they are established and in the absence of the original signal. Studies of cellular reprogramming in the germline and early embryogenesis [19][20][21][22] , during induced pluripotency (iPS) 23,24 , or upon somatic nuclear transfer 25,26 have shown that chromatin and DNA methylation act as important 'epigenetic barriers' (Fig. 1) that prevent changes in gene expression and cell identity.…”

Section: Review Researchmentioning

confidence: 99%

Advances in epigenetics link genetics to the environment and disease

Cavalli

Heard

2019

Nature

1,025

696

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Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health.

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“…EED conditional knockout ESCs that express a doxycycline-sensitive Eed4 transgene (Eed4 TG ) in an Eed −/− background were treated with 1 µg/mL doxycycline (DOX) for 14 d to disrupt PRC2 complex and function, as previously described (Ura et al 2008;Tavares et al 2012). SV40-immortalized Ring1 −/− ;Rnf2 fl/fl mouse embryonic fibroblasts (MEFs) (Endoh et al 2012;Jullien et al 2017) were grown in DMEM supplemented with 7% FBS and penicillin/streptomycin and maintained in culture for up to 10 passages. Ring1 −/− ;Rnf2 fl/fl MEFs were treated with 800 nM TAM for 96 h to ablate RNF2 levels.…”

Section: Cell Culture and Linesmentioning

confidence: 99%

Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes

et al. 2018

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Polycomb group (PcG) proteins are transcriptional repressors that play important roles in regulating gene expression during animal development. In vitro experiments have shown that PcG protein complexes can compact chromatin to limit the activity of chromatin remodeling enzymes and access of the transcriptional machinery to DNA. In fitting with these ideas, gene promoters associated with PcG proteins have been reported to be less accessible than other gene promoters. However, it remains largely untested in vivo whether PcG proteins define chromatin accessibility or other chromatin features. To address this important question, we examine the chromatin accessibility and nucleosome landscape at PcG protein-bound promoters in mouse embryonic stem cells using the assay for transposase accessible chromatin (ATAC)-seq. Combined with genetic ablation strategies, we unexpectedly discover that although PcG protein-occupied gene promoters exhibit reduced accessibility, this does not rely on PcG proteins. Instead, the Polycomb repressive complex 1 (PRC1) appears to play a unique role in driving elevated nucleosome occupancy and decreased nucleosomal spacing in Polycomb chromatin domains. Our new genome-scale observations argue, in contrast to the prevailing view, that PcG proteins do not significantly affect chromatin accessibility and highlight an underappreciated complexity in the relationship between chromatin accessibility, the nucleosome landscape, and PcG-mediated transcriptional repression.

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Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways

Cited by 41 publications

References 48 publications

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

H3K27me3 is an epigenetic barrier while KDM6A overexpression improves nuclear reprogramming efficiency

Advances in epigenetics link genetics to the environment and disease

Polycomb repressive complex 1 shapes the nucleosome landscape but not accessibility at target genes

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