Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton.
Heads, Shoulders, Elbows, Knees, and Toes: Modular Gdf5 Enhancers Control Different Joints in the Vertebrate Skeleton.
复制标题
DOI：
10.1371/journal.pgen.1006454
复制
发表时间：
2016-11
期刊：
影响因子：
4.5
通讯作者：
Kingsley DM
中科院分区：
文献类型：
--
作者：
Chen H;Capellini TD;Schoor M;Mortlock DP;Reddi AH;Kingsley DM
滑膜关节对于脊椎动物的支撑和运动至关重要，也是人类严重骨骼缺陷和退行性疾病的常见部位。生长和分化因子 5 (Gdf5) 是关节形成的最早标志物之一，是小鼠和人类正常关节发育所必需的，并且与欧亚人群常见骨关节炎的风险存在遗传相关性。在这里，我们系统地调查了小鼠 Gdf5 基因中控制滑膜关节表达的调控元件。我们确定了控制轴向组织、四肢近端关节和远端关节以及复合关节（如肘）的非常特定的子集中表达的基因座的不同区域。 Gdf5 调节增强子内预测的转录因子结合位点是特定关节中表达所必需的。控制不同关节中Gdf5表达的多个增强子分布在超过一百个碱基的DNA中，包括Gdf5编码外显子的上游和下游区域。小鼠的功能救援测试证实，需要较大的侧翼区域来恢复正常的关节形成和模式。这些增强子的直系同源物遍布先前与人类常见骨关节炎风险相关的大基因组区域。 Gdf5 的大量模块化增强子为研究脊椎动物关节模式的空间特异性提供了新的基础，也为可能影响人类骨关节炎风险的调控区域提供了新的候选者。髋关节和膝关节等关节对于动物的支撑和运动至关重要，也是关节炎等严重人类疾病的常见部位。生长和分化因子 5 (Gdf5) 基因是正常关节形成所必需的，并且与欧亚人常见关节炎的风险有关。在这里，我们调查了小鼠基因中控制关节形成位点条纹中 Gdf5 表达模式的调控信息。该基因不具有驱动所有关节表达的单一调控序列。相反，Gdf5 有多种不同的控制序列，对头部、脊柱、肩部、肘部、腕部、髋部、膝部和手指关节表现出惊人的特异性。救援实验表明，Gdf5 突变体需要多个控制序列来恢复正常的关节形成。最初在小鼠中发现的联合控制序列也存在于人类中，它们在胎儿发育和产后生命期间被标记为活跃区域，并映射到与人类关节炎风险相关的大区域。现在可以研究人类 GDF5 控制序列中的调控变异，以了解它们在改变骨骼特定位置的关节发育或疾病风险方面的潜在作用。
Synovial joints are crucial for support and locomotion in vertebrates, and are the frequent site of serious skeletal defects and degenerative diseases in humans. Growth and differentiation factor 5 (Gdf5) is one of the earliest markers of joint formation, is required for normal joint development in both mice and humans, and has been genetically linked to risk of common osteoarthritis in Eurasian populations. Here, we systematically survey the mouse Gdf5 gene for regulatory elements controlling expression in synovial joints. We identify separate regions of the locus that control expression in axial tissues, in proximal versus distal joints in the limbs, and in remarkably specific sub-sets of composite joints like the elbow. Predicted transcription factor binding sites within Gdf5 regulatory enhancers are required for expression in particular joints. The multiple enhancers that control Gdf5 expression in different joints are distributed over a hundred kilobases of DNA, including regions both upstream and downstream of Gdf5 coding exons. Functional rescue tests in mice confirm that the large flanking regions are required to restore normal joint formation and patterning. Orthologs of these enhancers are located throughout the large genomic region previously associated with common osteoarthritis risk in humans. The large array of modular enhancers for Gdf5 provide a new foundation for studying the spatial specificity of joint patterning in vertebrates, as well as new candidates for regulatory regions that may also influence osteoarthritis risk in human populations. Joints, such as the hip and knee, are crucial for support and locomotion in animals, and are the frequent sites of serious human diseases such as arthritis. The Growth and differentiation factor 5 (Gdf5) gene is required for normal joint formation, and has been linked to risk of common arthritis in Eurasians. Here, we surveyed the mouse gene for the regulatory information that controls Gdf5's expression pattern in stripes at sites of joint formation. The gene does not have a single regulatory sequence that drives expression in all joints. Instead, Gdf5 has multiple different control sequences that show striking specificity for joints in the head, vertebral column, shoulder, elbow, wrist, hip, knee, and digits. Rescue experiments show that multiple control sequences are required to restore normal joint formation in Gdf5 mutants. The joint control sequences originally found in mice are also present in humans, where they are marked as active regions during fetal development and post-natal life, and map to a large region associated with arthritis risk in human populations. Regulatory variants in the human GDF5 control sequences can now be studied for their potential role in altering joint development or disease risk at particular locations in the skeleton.
登录
查看更多内容
影响因子：
--
作者：
Evangelou, Evangelos;Chapman, Kay;Meulenbelt, Ingrid;Karassa, Fotini B.;Loughlin, John;Carr, Andrew;Doherty, Michael;Doherty, Sally;Gomez-Reino, Juan J.;Gonzalez, Antonio;Halldorsson, Bjarni V.;Hauksson, Valdimar B.;Hofman, Albert;Hart, Deborah J.;Ikegawa, Shiro;Ingvarsson, Thorvaldur;Jiang, Qing;Jonsdottir, Ingileif;Jonsson, Helgi;Kerkhof, Hanneke J. M.;Kloppenburg, Margreet;Lane, Nancy E.;Li, Jia;Lories, Rik J.;van Meurs, Joyce B. J.;Nakki, Annu;Nevitt, Michael C.;Rodriguez-Lopez, Julio;Shi, Dongquan;Slagboom, Eline;Stefansson, Kari;Tsezou, Aspasia;Wallis, Gillian A.;Watson, Christopher M.;Spector, Tim D.;Uitterlinden, Andre G.;Valdes, Ana M.;Ioannidis, John P. A.
通讯作者：
Ioannidis, John P. A.
DOI：
10.1038/ejhg.2012.197
发表时间：
2013-05
期刊：
European journal of human genetics : EJHG
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.1
作者：
Guenther, Catherine A.;Wang, Zhen;Li, Emma;Tran, Misha C.;Logan, Catriona Y.;Nusse, Roel;Pantalena-Filho, Luiz;Yang, George P.;Kingsley, David M.
通讯作者：
Kingsley, David M.
影响因子：
--
作者：
Egli RJ;Southam L;Wilkins JM;Lorenzen I;Pombo-Suarez M;Gonzalez A;Carr A;Chapman K;Loughlin J
通讯作者：
Loughlin J
影响因子：
3.5
作者：
Chapman, Kay;Takahashi, Atsushi;Ikegawa, Shiro
通讯作者：
Ikegawa, Shiro