Epigenetic engineering shows H3K4me2 is required for HJURP targeting and CENP-A assembly on a synthetic human kinetochore

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  • Jan H Bergmann
    Wellcome Trust Centre for Cell Biology, University of Edinburgh; Edinburgh Scotland UK
  • Mariluz Gómez Rodríguez
    Instituto Gulbenkian de Ciência; Oeiras Portugal
  • Nuno M C Martins
    Wellcome Trust Centre for Cell Biology, University of Edinburgh; Edinburgh Scotland UK
  • Hiroshi Kimura
    Biomolecular Networks Laboratories Group, Graduate School of Frontier Biosciences, Osaka University; Osaka Japan
  • David A Kelly
    Wellcome Trust Centre for Cell Biology, University of Edinburgh; Edinburgh Scotland UK
  • Hiroshi Masumoto
    Laboratory of Cell Engineering, Kazusa DNA Research Institute; Chiba Japan
  • Vladimir Larionov
    Laboratory of Molecular Pharmacology, National Institutes of Health; Bethesda MD USA
  • Lars E T Jansen
    Instituto Gulbenkian de Ciência; Oeiras Portugal
  • William C Earnshaw
    Wellcome Trust Centre for Cell Biology, University of Edinburgh; Edinburgh Scotland UK

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  • H3K4me2 and kinetochore maintenance

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Description

Kinetochores assemble on distinct 'centrochromatin' containing the histone H3 variant CENP-A and interspersed nucleosomes dimethylated on H3K4 (H3K4me2). Little is known about how the chromatin environment at active centromeres governs centromeric structure and function. Here, we report that centrochromatin resembles K4-K36 domains found in the body of some actively transcribed housekeeping genes. By tethering the lysine-specific demethylase 1 (LSD1), we specifically depleted H3K4me2, a modification thought to have a role in transcriptional memory, from the kinetochore of a synthetic human artificial chromosome (HAC). H3K4me2 depletion caused kinetochores to suffer a rapid loss of transcription of the underlying α-satellite DNA and to no longer efficiently recruit HJURP, the CENP-A chaperone. Kinetochores depleted of H3K4me2 remained functional in the short term, but were defective in incorporation of CENP-A, and were gradually inactivated. Our data provide a functional link between the centromeric chromatin, α-satellite transcription, maintenance of CENP-A levels and kinetochore stability.

Journal

  • The EMBO Journal

    The EMBO Journal 30 (2), 328-340, 2010-12-14

    Springer Science and Business Media LLC

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