A Read/Write Mechanism Connects p300 Bromodomain Function to H2A.Z Acetylation

Yolanda Colino-Sanguino; Evan M Cornett; David Moulder; Grady C Smith; Joel Hrit; Eric Cordeiro-Spinetti; Robert M Vaughan; Krzysztof Krajewski; Scott B Rothbart; Susan J Clark; Fátima Valdés-Mora

doi:10.1016/j.isci.2019.10.053

A Read/Write Mechanism Connects p300 Bromodomain Function to H2A.Z Acetylation

iScience. 2019 Nov 22:21:773-788. doi: 10.1016/j.isci.2019.10.053. Epub 2019 Oct 31.

Affiliations

¹ Histone Variants Group, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, University of NSW Sydney, Sydney, NSW, Australia.
² Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
³ Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, University of NSW Sydney, Sydney, NSW, Australia.
⁴ Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
⁵ Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
⁶ Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA. Electronic address: scott.rothbart@vai.org.
⁷ Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, University of NSW Sydney, Sydney, NSW, Australia. Electronic address: s.clark@garvan.org.au.
⁸ Histone Variants Group, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; Epigenetics Research Laboratory, Genomics and Epigenetics Division, Garvan Institute of Medical Research, Sydney, NSW, Australia; St. Vincent's Clinical School, University of NSW Sydney, Sydney, NSW, Australia. Electronic address: f.valdesmora@garvan.org.au.

Abstract

Acetylation of the histone variant H2A.Z (H2A.Zac) occurs at active regulatory regions associated with gene expression. Although the Tip60 complex is proposed to acetylate H2A.Z, functional studies suggest additional enzymes are involved. Here, we show that p300 acetylates H2A.Z at multiple lysines. In contrast, we found that although Tip60 does not efficiently acetylate H2A.Z in vitro, genetic inhibition of Tip60 reduces H2A.Zac in cells. Importantly, we found that interaction between the p300-bromodomain and H4 acetylation (H4ac) enhances p300-driven H2A.Zac. Indeed, H2A.Zac and H4ac show high genomic overlap, especially at active promoters. We also reveal unique chromatin features and transcriptional states at enhancers correlating with co-occurrence or exclusivity of H4ac and H2A.Zac. We propose that differential H4 and H2A.Z acetylation signatures can also define the enhancer state. In conclusion, we show both Tip60 and p300 contribute to H2A.Zac and reveal molecular mechanisms of writer/reader crosstalk between H2A.Z and H4 acetylation through p300.

Keywords: Biochemistry; Biological Sciences; Cell Biology; Molecular Biology.

Grants and funding

R35 GM124736/GM/NIGMS NIH HHS/United States