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First published online May 9, 2008
doi: 10.1242/10.1242/dev.017160

Development 135, 1935-1946 (2008)
Published by The Company of Biologists 2008
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The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity

Kathrin Laue1,*, Sylvain Daujat2,*, Justin Gage Crump3, Nikki Plaster1,{dagger}, Henry H. Roehl4 Tübingen 2000 Screen Consortium{ddagger}, Charles B. Kimmel5, Robert Schneider2,§, Matthias Hammerschmidt1,6,§§

1 Georges-Koehler-Laboratory and
2 Hans-Spemann-Laboratory, Max-Planck-Institute of Immunobiology, Stuebeweg 51, D-79108 Freiburg, Germany.
3 Center for Stem Cell and Regenerative Medicine, USC Keck School of Medicine, Los Angeles, CA 90033, USA.
4 Centre of Developmental and Biomedical Genetics, University of Sheffield, Sheffield S10 2TN, UK.
5 Institute of Neuroscience, 1254 University of Oregon, Eugene, OR, USA.
6 Institute for Developmental Biology, University of Cologne, D-50923 Cologne, Germany.

§ Author for correspondence (e-mail: schneiderr{at}immunbio.mpg.de)

§§ Alternate author for correspondence (e-mail: hammerschmid{at}immunbio.mpg.de)

Accepted 27 March 2008

The Trithorax group (TrxG) is composed of diverse, evolutionary conserved proteins that form chromatin-associated complexes accounting for epigenetic transcriptional memory. However, the molecular mechanisms by which particular loci are marked for reactivation after mitosis are only partially understood. Here, based on genetic analyses in zebrafish, we identify the multidomain protein Brpf1 as a novel TrxG member with a central role during development. brpf1 mutants display anterior transformations of pharyngeal arches due to progressive loss of anterior Hox gene expression. Brpf1 functions in association with the histone acetyltransferase Moz (Myst3), an interaction mediated by the N-terminal domain of Brpf1, and promotes histone acetylation in vivo. Brpf1 recruits Moz to distinct sites of active chromatin and remains at chromosomes during mitosis, mediated by direct histone binding of its bromodomain, which has a preference for acetylated histones, and its PWWP domain, which binds histones independently of their acetylation status. This is the first demonstration of histone binding for PWWP domains. Mutant analyses further show that the PWWP domain is absolutely essential for Brpf1 function in vivo. We conclude that Brpf1, coordinated by its particular set of domains, acts by multiple mechanisms to mediate Moz-dependent histone acetylation and to mark Hox genes for maintained expression throughout vertebrate development.

Key words: Brpf1, Bromodomain, PWWP domain, Moz, Hox gene expression, Craniofacial development, Cranial neural crest, Pharyngeal arch, Anterior-posterior patterning, Homeotic transformation, Zebrafish






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