2. Academic Validation
  3. Gene Resistance to Transcriptional Reprogramming following Nuclear Transfer Is Directly Mediated by Multiple Chromatin-Repressive Pathways

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

  • Mol Cell. 2017 Mar 2;65(5):873-884.e8. doi: 10.1016/j.molcel.2017.01.030.
Jerome Jullien 1,  Munender Vodnala 2,  Vincent Pasque 3,  Mami Oikawa 2,  Kei Miyamoto 4,  George Allen 2,  Sarah Anne David 5,  Vincent Brochard 5,  Stan Wang 6,  Charles Bradshaw 2,  Haruhiko Koseki 7,  Vittorio Sartorelli 8,  Nathalie Beaujean 5,  John Gurdon 2
Affiliations

Affiliations

  • 1 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK. Electronic address: [email protected].
  • 2 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
  • 3 Department of Development and Regeneration, KU Leuven, University of Leuven, Herestraat 49, 3000 Leuven, Belgium.
  • 4 Laboratory of Molecular Developmental Biology, Graduate School of Biology-Oriented Science and Technology, Kinki University, Wakayama 649-6493, Japan.
  • 5 UMR BDR, INRA, ENVA, Université Paris Saclay, 78350 Jouy en Josas, France.
  • 6 Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
  • 7 RIKEN Center for Integrative Medical Sciences, Laboratory for Developmental Genetics, North Research Building, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama City, Kanagawa 230-0045, Japan.
  • 8 Laboratory of Muscle Stem Cells and Gene Regulation, National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), NIH, Bethesda, MD 20892, USA.
PMID: 28257702 DOI: 10.1016/j.molcel.2017.01.030
Abstract

Understanding the mechanism of resistance of genes to reactivation will help improve the success of nuclear reprogramming. Using mouse embryonic fibroblast nuclei with normal or reduced DNA methylation in combination with chromatin modifiers able to erase H3K9me3, H3K27me3, and H2AK119ub1 from transplanted nuclei, we reveal the basis for resistance of genes to transcriptional reprogramming by oocyte factors. A majority of genes is affected by more than one type of treatment, suggesting that resistance can require repression through multiple epigenetic mechanisms. We classify resistant genes according to their sensitivity to 11 chromatin modifier combinations, revealing the existence of synergistic as well as adverse effects of chromatin modifiers on removal of resistance. We further demonstrate that the chromatin modifier USP21 reduces resistance through its H2AK119 deubiquitylation activity. Finally, we provide evidence that H2A ubiquitylation also contributes to resistance to transcriptional reprogramming in mouse nuclear transfer embryos.

Keywords

chromatin; epigenetic; nuclear transfer; oocyte; resistance; transcriptional reprogramming; xenopus.

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