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

• Published in: Nature communications Vol. 7; no. 1; p. 13465
• Main Authors: Shang, Wei-Hao, Hori, Tetsuya, Westhorpe, Frederick G., Godek, Kristina M., Toyoda, Atsushi, Misu, Sadahiko, Monma, Norikazu, Ikeo, Kazuho, Carroll, Christopher W., Takami, Yasunari, Fujiyama, Asao, Kimura, Hiroshi, Straight, Aaron F., Fukagawa, Tatsuo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 04-11-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/337/100/2285; 631/80/103/1966; 631/80/103/90; 82/83; Antibodies; Biochemistry; Biology; Chromosomes; Epigenetics; Genomes; Humanities and Social Sciences; multidisciplinary; Science; Science (multidisciplinary); United States > US; Japan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13465

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.
The deposition of histone H3 variant CENP-A bound with histone H4 is a key feature designating the centromere region of a chromosome. Here the authors show acetylation on residues K5 and K12 in histone H4, mediated by the RbAp46/48-Hat1 complex, is required for deposition of CENP-A-H4 into centromeres.