Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4
Growth and early postimplantation defects in mice deficient for the bromodomain-containing protein Brd4
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DOI：
10.1128/mcb.22.11.3794-3802.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Beddington, RSP
中科院分区：
文献类型：
--
作者：
Houzelstein, D;Bullock, SL;Beddington, RSP
在基因诱捕筛选中，我们回收了一个小鼠突变株系，其中插入产生了Brd 4基因的无效等位基因。Brd 4属于Fsh/Brd家族，这是一组结构相关的蛋白质，其特征在于两个溴结构域和一个末端外结构域的缔合。该家族的成员包括哺乳动物中的Brd 2/Ring 3/Fsrg 1、果蝇中的fs（1）h和酿酒酵母中的Bdf 1。Brd 4杂合子显示与增殖率降低相关的产前和产后生长缺陷。这些小鼠还表现出各种解剖学异常：头部畸形、缺乏皮下脂肪、白内障和异常肝细胞。在原代细胞培养中，杂合细胞也显示出降低的增殖速率和对甲磺酸甲酯的中度敏感性。Brd 4无效合子的胚胎在植入后不久死亡，并且在体外维持内细胞团的能力受到损害，这表明在基本细胞过程中发挥作用。最后，序列比较表明，Brd 4可能对应于Y. W. Jiang，P. Veschambre，H. Erdjument-Bromage，P. Tempst，J. W.科纳韦河C. Conaway和R. D. Kornberg（Proc. Natl. Acad. Sci. USA 95：8538-8543，1998），并根据该结果讨论了Brd 4突变体表型。总之，我们的研究结果提供了第一个遗传证据的FSH/Brd家族的成员在哺乳动物体内的作用。
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.