PWWP2A binds distinct chromatin moieties and interacts with an MTA1-specific core NuRD complex

Nat Commun. 2018 Oct 16;9(1):4300. doi: 10.1038/s41467-018-06665-5.

Stephanie Link ¹ ², Ramona M M Spitzer ¹ ², Maryam Sana ³, Mario Torrado ³, Moritz C Völker-Albert ¹, Eva C Keilhauer ⁴ ⁵, Thomas Burgold ⁶ ⁷, Sebastian Pünzeler ¹ ⁸, Jason K K Low ³, Ida Lindström ³, Andrea Nist ⁹, Catherine Regnard ¹, Thorsten Stiewe ⁹ ¹⁰, Brian Hendrich ⁶, Axel Imhof ¹ ¹¹, Matthias Mann ⁴ ¹¹, Joel P Mackay ³, Marek Bartkuhn ¹², Sandra B Hake ¹³ ¹⁴

Affiliations

1 Department of Molecular Biology, BioMedical Center (BMC), Ludwig-Maximilians-University Munich, 82152, Planegg-Martinsried, Germany.
2 Institute for Genetics, Justus-Liebig University Giessen, 35392, Giessen, Germany.
3 School of Life and Environmental Sciences, University of Sydney, New South Wales, 2006, Australia.
4 Department of Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, 82152, Martinsried, Germany.
5 Coriolis Pharma, Fraunhoferstr. 18B, 82152, Planegg, Germany.
6 Wellcome Trust - MRC Stem Cell Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QR, UK.
7 Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA, UK.
8 Coparion GmbH & Co. KG, Charles-de-Gaulle-Platz 1d, 50679, Cologne, Germany.
9 Genomics Core Facility, Philipps-University Marburg, 35043, Marburg, Germany.
10 Institute for Molecular Oncology, Philipps-University Marburg, 35043, Marburg, Germany.
11 Center for Integrated Protein Science Munich (CIPSM), 81377, Munich, Germany.
12 Institute for Genetics, Justus-Liebig University Giessen, 35392, Giessen, Germany. marek.bartkuhn@gen.bio.uni-giessen.
13 Institute for Genetics, Justus-Liebig University Giessen, 35392, Giessen, Germany. sandra.hake@gen.bio.uni-giessen.de.
14 Center for Integrated Protein Science Munich (CIPSM), 81377, Munich, Germany. sandra.hake@gen.bio.uni-giessen.de.

PMID: 30327463 DOI: 10.1038/s41467-018-06665-5

Abstract

Chromatin structure and function is regulated by reader proteins recognizing histone modifications and/or histone variants. We recently identified that PWWP2A tightly binds to H2A.Z-containing nucleosomes and is involved in mitotic progression and cranial-facial development. Here, using in vitro assays, we show that distinct domains of PWWP2A mediate binding to free linker DNA as well as H3K36me3 nucleosomes. In vivo, PWWP2A strongly recognizes H2A.Z-containing regulatory regions and weakly binds H3K36me3-containing gene bodies. Further, PWWP2A binds to an MTA1-specific subcomplex of the NuRD complex (M1HR), which consists solely of MTA1, HDAC1, and RBBP4/7, and excludes CHD, GATAD2 and MBD proteins. Depletion of PWWP2A leads to an increase of acetylation levels on H3K27 as well as H2A.Z, presumably by impaired chromatin recruitment of M1HR. Thus, this study identifies PWWP2A as a complex chromatin-binding protein that serves to direct the deacetylase complex M1HR to H2A.Z-containing chromatin, thereby promoting changes in histone acetylation levels.

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