Eid Wassim, Opitz Lennart, Biason-Lauber Anna
Division of Endocrinology (W.E., A.B.-L.), Department of Medicine, University of Fribourg, 1700 Fribourg, Switzerland; and Functional Genomics Center Zurich (L.O.), University of Zurich/ETHZ, 8057 Zurich, Switzerland.
Mol Endocrinol. 2015 Feb;29(2):247-57. doi: 10.1210/me.2014-1339. Epub 2015 Jan 8.
Chromobox homolog 2 (CBX2) is a chromatin modifier that plays an important role in sexual development and its disorders (disorders of sex development [DSD]), yet the exact rank and function of human CBX2 in this pathway remains unclear. Here, we performed large-scale mapping and analysis of in vivo target loci of the protein CBX2 in Sertoli-like NT-2D1 cells, using the DNA adenine methyltransferase identification technique. We identified close to 1600 direct targets for CBX2. Intriguingly, validation of selected candidate genes using qRT-PCR in cells overexpressing CBX2 or in which CBX2 has been knocked down indicated that several CBX2-responsive genes encode proteins that are involved in DSD. We further validated these effects on the candidate genes using a mutated CBX2 causing DSD in human patient. Overall, our findings suggest that CBX2 role in the sex development cascade is to stimulate the male pathway and concurrently inhibit the female pathway. These data provide fundamental insights into potential etiology of DSD.
染色质盒同源物2（CBX2）是一种染色质修饰因子，在性发育及其疾病（性发育障碍[DSD]）中起重要作用，但人类CBX2在该途径中的具体地位和功能仍不清楚。在此，我们利用DNA腺嘌呤甲基转移酶识别技术，对类支持细胞NT-2D1中蛋白质CBX2的体内靶位点进行了大规模定位和分析。我们鉴定出了近1600个CBX2的直接靶点。有趣的是，在过表达CBX2或CBX2已被敲低的细胞中，使用qRT-PCR对选定的候选基因进行验证，结果表明几个CBX2反应基因编码参与DSD的蛋白质。我们进一步使用在人类患者中导致DSD的突变CBX2验证了对候选基因的这些影响。总体而言，我们的研究结果表明，CBX2在性发育级联反应中的作用是刺激男性途径并同时抑制女性途径。这些数据为DSD的潜在病因提供了基本见解。
