Abnormal X chromosome inactivation and sex-specific gene dysregulation after ablation of FBXL10.
Abnormal X chromosome inactivation and sex-specific gene dysregulation after ablation of FBXL10.
复制标题
FBXL10消融后，异常的X染色体失活和性别特异性基因失调。
DOI：
10.1186/s13072-016-0069-1
复制
发表时间：
2016
影响因子：
3.9
通讯作者：
Bestor TH
中科院分区：
文献类型：
--
作者：
Boulard M;Edwards JR;Bestor TH
哺乳动物基因组中几乎所有富含CpG的启动子都与多结构域FBXL 10蛋白（也称为KDM 2B、JHDM 1B、CXXC 2和NDY 1）结合。FBXL 10表达为两种亚型：FBXL 10 -1，一种较长的形式，含有N-末端组蛋白脱甲基酶结构域，C-末端F-盒，CXXC，PHD，RING和富含亮氨酸的重复结构域，和FBXL 10 -2，一种较短的形式，起始于一个替代的内部外显子，缺乏组蛋白脱甲基酶结构域，但保留所有其他注释的结构域。据报道，Fbxl 10 -1的选择性缺失产生低突变率和可变表型;大多数突变动物基本正常。我们构建了Fbxl 10 -2无效但Fbxl 10 -1为野生型或Fbxl 10 - 1和Fbxl 10 -2均无效的突变小鼠品系。Fbxl 10 -2的缺失（以不干扰Fbxl 10 -1表达的方式）产生了与Fbxl 10 -1突变体非常不同的表型，具有颅面异常、神经管缺陷和增加的致死率，特别是在女性中。缺乏FBXL 10 -1和FBXL 10 -2的突变体表现出胚胎致死性，甚至更极端的性二型性，在突变的雌性胚胎中具有更严重的基因失调。X连锁基因是最严重的失调，有显着的Xist突变体女性的过度表达，虽然基因编码的因素，结合Xist RNA在突变体女性相比，男性胚胎的下调。FBXL 10是Xist基因的正常表达和功能以及与Xist RNA相关的蛋白质的正常表达所需的第一个因子;提出FBXL 10协调Xist RNA的表达和与该RNA相关的蛋白质。FBXL 10的功能在很大程度上不依赖于长型蛋白质的组蛋白脱甲基酶活性。本文的在线版本（doi：10.1186/s13072-016-0069-1）包含补充材料，可供授权用户使用。
Almost all CpG-rich promoters in the mammalian genome are bound by the multidomain FBXL10 protein (also known as KDM2B, JHDM1B, CXXC2, and NDY1). FBXL10 is expressed as two isoforms: FBXL10-1, a longer form that contains an N-terminal histone demethylase domain with C-terminal F-box, CXXC, PHD, RING, and leucine-rich repeat domains, and FBXL10-2, a shorter form that initiates at an alternative internal exon and which lacks the histone demethylase domain but retains all other annotated domains. Selective deletion of Fbxl10-1 had been reported to produce a low penetrance and variable phenotype; most of the mutant animals were essentially normal. We constructed mutant mouse strains that were either null for Fbxl10-2 but wild type for Fbxl10-1 or null for both Fbxl10-1 and Fbxl10-2. Deletion of Fbxl10-2 (in a manner that does not perturb expression of Fbxl10-1) produced a phenotype very different from the Fbxl10-1 mutant, with craniofacial abnormalities, neural tube defects, and increased lethality, especially in females. Mutants that lacked both FBXL10-1 and FBXL10-2 showed embryonic lethality and even more extreme sexual dimorphism, with more severe gene dysregulation in mutant female embryos. X-linked genes were most severely dysregulated, and there was marked overexpression of Xist in mutant females although genes that encode factors that bind to Xist RNA were globally downregulated in mutant female as compared to male embryos. FBXL10 is the first factor shown to be required both for the normal expression and function of the Xist gene and for normal expression of proteins that associate with Xist RNA; it is proposed that FBXL10 coordinates the expression of Xist RNA with proteins that associate with this RNA. The function of FBXL10 is largely independent of the histone demethylase activity of the long form of the protein. The online version of this article (doi:10.1186/s13072-016-0069-1) contains supplementary material, which is available to authorized users.