Acetylation of histone H4 lysine 5 and 12 is required for CENP-A deposition into centromeres

Wei-Hao Shang, Tetsuya Hori, Frederick G. Westhorpe, Kristina M. Godek, Atsushi Toyoda, Sadahiko Misu, Norikazu Monma, Kazuho Ikeo, Christopher W. Carroll, Yasunari Takami, Asao Fujiyama, Hiroshi Kimura, Aaron F. Straight and Tatsuo Fukagawa ()
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Wei-Hao Shang: Graduate School of Frontier Biosciences, Osaka University
Tetsuya Hori: Graduate School of Frontier Biosciences, Osaka University
Frederick G. Westhorpe: Stanford University Medical School
Kristina M. Godek: Geisel School of Medicine, Dartmouth College
Atsushi Toyoda: Comparative Genomics Laboratory, National Institute of Genetics
Sadahiko Misu: DNA Data Analysis Laboratory, National Institute of Genetics
Norikazu Monma: DNA Data Analysis Laboratory, National Institute of Genetics
Kazuho Ikeo: DNA Data Analysis Laboratory, National Institute of Genetics
Christopher W. Carroll: Yale University School of Medicine
Yasunari Takami: Section of Biochemistry and Molecular Biology, University of Miyazaki
Asao Fujiyama: Comparative Genomics Laboratory, National Institute of Genetics
Hiroshi Kimura: Cell Biology Unit, Institute of Innovative Research, Tokyo Institute of Technology
Aaron F. Straight: Stanford University Medical School
Tatsuo Fukagawa: Graduate School of Frontier Biosciences, Osaka University

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: Abstract Centromeres are specified epigenetically through the deposition of the centromere-specific histone H3 variant CENP-A. However, how additional epigenetic features are involved in centromere specification is unknown. Here, we find that histone H4 Lys5 and Lys12 acetylation (H4K5ac and H4K12ac) primarily occur within the pre-nucleosomal CENP-A–H4–HJURP (CENP-A chaperone) complex, before centromere deposition. We show that H4K5ac and H4K12ac are mediated by the RbAp46/48–Hat1 complex and that RbAp48-deficient DT40 cells fail to recruit HJURP to centromeres and do not incorporate new CENP-A at centromeres. However, C-terminally-truncated HJURP, that does not bind CENP-A, does localize to centromeres in RbAp48-deficient cells. Acetylation-dead H4 mutations cause mis-localization of the CENP-A–H4 complex to non-centromeric chromatin. Crucially, CENP-A with acetylation-mimetic H4 was assembled specifically into centromeres even in RbAp48-deficient DT40 cells. We conclude that H4K5ac and H4K12ac, mediated by RbAp46/48, facilitates efficient CENP-A deposition into centromeres.

Date: 2016
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DOI: 10.1038/ncomms13465

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