Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders
Chromatin remodeling by the CHD7 protein is impaired by mutations that cause human developmental disorders
复制标题
DOI：
10.1073/pnas.1213825109
复制
发表时间：
2012-11-20
影响因子：
11.1
通讯作者：
Kingston, Robert E.
中科院分区：
文献类型：
--
作者：
Bouazoune, Karim;Kingston, Robert E.
CHD 7基因突变导致人类发育障碍，包括CHARGE综合征。在模式生物中的遗传研究进一步确立了CHD 7作为脊椎动物发育的中心调节因子。CHD 7蛋白的功能分析由于其大尺寸而受到阻碍。我们使用双标签系统纯化完整的重组CHD 7蛋白，发现它是一个ATP依赖的核小体重塑因子。生化分析表明，CHD 7具有不同于SWI/SNF-和ISWI-型重塑的特征。进一步的研究表明，CHD 7患者突变的后果范围从轻微到完全失活的重塑活动，并导致蛋白质截短的氨基酸1899的CHD 7上游的突变可能会导致一个亚型表型重塑。我们认为核小体重塑是CHD 7在发育过程中的一个关键功能，并为预测疾病突变对该功能的影响提供了分子基础。
Mutations in the CHD7 gene cause human developmental disorders including CHARGE syndrome. Genetic studies in model organisms have further established CHD7 as a central regulator of vertebrate development. Functional analysis of the CHD7 protein has been hampered by its large size. We used a dual-tag system to purify intact recombinant CHD7 protein and found that it is an ATP-dependent nucleosome remodeling factor. Biochemical analyses indicate that CHD7 has characteristics distinct from SWI/SNF- and ISWI-type remodelers. Further investigations show that CHD7 patient mutations have consequences that range from subtle to complete inactivation of remodeling activity, and that mutations leading to protein truncations upstream of amino acid 1899 of CHD7 are likely to cause a hypomorphic phenotype for remodeling. We propose that nucleosome remodeling is a key function for CHD7 during developmental processes and provide a molecular basis for predicting the impact of disease mutations on that function.