Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4.
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.
Houzelstein
Denis
D
Laboratory of Mammalian Development, Medical Research Council, National Institute for Medical Research, London NW7 1AA, United Kingdom. houzelstein@ijm.jussieu.fr
Bullock
Simon L
SL
Lynch
Denise E
DE
Grigorieva
Elena F
EF
Wilson
Valerie A
VA
Beddington
Rosa S P
RS
D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002874:Chromosome Mapping; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics / Q000502:physiology*; D005091:Exons; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D010641:Phenotype; D011247:Pregnancy; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors; D014158:Transcription, Genetic; D000092468:Bromodomain Containing Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C486694:Brd4 protein, mouse