Affiliation:
1. Laboratory of Mammalian Development
2. Laboratory of Developmental Neurobiology, Medical Research Council, National Institute for Medical Research, London NW7 1AA, United Kingdom
Abstract
ABSTRACT
In a gene trap screen we recovered a mouse mutant line in which an insertion generated a null allele of the
Brd4
gene. Brd4 belongs to the Fsh/Brd family, a group of structurally related proteins characterized by the association of two bromodomains and one extraterminal domain. Members of this family include Brd2/Ring3/Fsrg1 in mammals, fs(1)h in
Drosophila
, and Bdf1 in
Saccharomyces cerevisiae
.
Brd4
heterozygotes display pre- and postnatal growth defects associated with a reduced proliferation rate. These mice also exhibit a variety of anatomical abnormalities: head malformations, absence of subcutaneous fat, cataracts, and abnormal liver cells. In primary cell cultures, heterozygous cells also display reduced proliferation rates and moderate sensitivity to methyl methanesulfonate. Embryos nullizygous for
Brd4
die shortly after implantation and are compromised in their ability to maintain an inner cell mass in vitro, suggesting a role in fundamental cellular processes. Finally, sequence comparisons suggest that Brd4 is likely to correspond to the Brd-like element of the mediator of transcriptional regulation isolated by Y. W. Jiang, P. Veschambre, H. Erdjument-Bromage, P. Tempst, J. W. Conaway, R. C. Conaway, and R. D. Kornberg (Proc. Natl. Acad. Sci. USA
95:
8538-8543, 1998) and the
Brd4
mutant phenotype is discussed in light of this result. Together, our results provide the first genetic evidence for an in vivo role in mammals for a member of the Fsh/Brd family.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
265 articles.
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