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Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance

Author

Listed:
  • Oscar Molina

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

  • Giulia Vargiu

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

  • Maria Alba Abad

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

  • Alisa Zhiteneva

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

  • A. Arockia Jeyaprakash

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

  • Hiroshi Masumoto

    (Laboratory of Cell Engineering, Kazusa DNA research Institute)

  • Natalay Kouprina

    (Genome Structure and Function Group, Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health)

  • Vladimir Larionov

    (Genome Structure and Function Group, Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health)

  • William C. Earnshaw

    (Wellcome Trust Centre for Cell Biology, University of Edinburgh)

Abstract

Centromeres consist of specialized centrochromatin containing CENP-A nucleosomes intermingled with H3 nucleosomes carrying transcription-associated modifications. We have designed a novel synthetic biology ‘in situ epistasis’ analysis in which H3 dimethylated on lysine 4 (H3K4me2) demethylase LSD2 plus synthetic modules with competing activities are simultaneously targeted to a synthetic alphoidtetO HAC centromere. This allows us to uncouple transcription from histone modifications at the centromere. Here, we report that H3K4me2 loss decreases centromeric transcription, CENP-A assembly and stability and causes spreading of H3K9me3 across the HAC, ultimately inactivating the centromere. Surprisingly, CENP-28/Eaf6-induced transcription of the alphoidtetO array associated with H4K12 acetylation does not rescue the phenotype, whereas p65-induced transcription associated with H3K9 acetylation does rescue. Thus mitotic transcription plus histone modifications including H3K9ac constitute the ‘epigenetic landscape’ allowing CENP-A assembly and centrochromatin maintenance. H3K4me2 is required for the transcription and H3K9ac may form a barrier to prevent heterochromatin spreading and kinetochore inactivation at human centromeres.

Suggested Citation

  • Oscar Molina & Giulia Vargiu & Maria Alba Abad & Alisa Zhiteneva & A. Arockia Jeyaprakash & Hiroshi Masumoto & Natalay Kouprina & Vladimir Larionov & William C. Earnshaw, 2016. "Epigenetic engineering reveals a balance between histone modifications and transcription in kinetochore maintenance," Nature Communications, Nature, vol. 7(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13334
    DOI: 10.1038/ncomms13334
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    Cited by:

    1. Catherine Naughton & Covadonga Huidobro & Claudia R. Catacchio & Adam Buckle & Graeme R. Grimes & Ryu-Suke Nozawa & Stefania Purgato & Mariano Rocchi & Nick Gilbert, 2022. "Human centromere repositioning activates transcription and opens chromatin fibre structure," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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