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

Oscar Molina, Giulia Vargiu, Maria Alba Abad, Alisa Zhiteneva, A. Arockia Jeyaprakash, Hiroshi Masumoto, Natalay Kouprina, Vladimir Larionov and William C. Earnshaw ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13334

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