The multidomain protein Brpf1 binds histones and is required for Hox gene expression and segmental identity.
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.
Laue
Kathrin
K
Georges-Koehler-Laboratory, Max-Planck-Institute of Immunobiology, Freiburg, Germany.
Daujat
Sylvain
S
Crump
Justin Gage
JG
Plaster
Nikki
N
Roehl
Henry H
HH
Kimmel
Charles B
CB
Schneider
Robert
R
Hammerschmidt
Matthias
M
D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001934:Branchial Region / Q000033:anatomy & histology / Q000254:growth & development / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D017403:In Situ Hybridization; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000092468:Bromodomain Containing Proteins
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D002843:Chromatin; D004268:DNA-Binding Proteins; D051548:Histone Acetyltransferases; D006657:Histones; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D029961:Zebrafish Proteins; C000597967:BRPF1 protein, mouse; D000092468:Bromodomain Containing Proteins; C531509:Brpf1 protein, zebrafish; C513434:kat6a protein, zebrafish