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
Affiliations
Yolanda Colino-Sanguino
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
Evan M. Cornett
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
David Moulder
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
Grady C. Smith
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
Joel Hrit
Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
Eric Cordeiro-Spinetti
Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
Robert M. Vaughan
Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA
Krzysztof Krajewski
Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Scott B. Rothbart
Center for Epigenetics, Van Andel Institute, Grand Rapids, MI, USA; Corresponding author
Susan J. Clark
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; Corresponding author
Fátima Valdés-Mora
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; Corresponding author
Summary: 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. : Biological Sciences; Biochemistry; Molecular Biology; Cell Biology Subject Areas: Biological Sciences, Biochemistry, Molecular Biology, Cell Biology
