BCOR regulates mesenchymal stem cell function by epigenetic mechanisms.
BCOR regulates mesenchymal stem cell function by epigenetic mechanisms.
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DOI：
10.1038/ncb1913
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发表时间：
2009-08
影响因子：
21.3
通讯作者：
Wang, Cun-Yu
中科院分区：
文献类型：
--
作者：
Fan, Zhipeng;Yamaza, Takayoshi;Lee, Janice S.;Yu, Jinhua;Wang, Songlin;Fan, Guoping;Shi, Songtao;Wang, Cun-Yu
BCOR（BCL-6 co-repressor）通过与BCL-6相互作用抑制基因转录。BCOR突变导致眼-面-心-牙（OFCD）综合征，其特征是犬齿具有极长的牙根、先天性白内障、颅面缺陷和先天性心脏病。在这里，我们发现BCOR突变增加了从OFCD患者分离的间充质干细胞（MSCs）的成骨/牙本质潜能，为牙根异常生长提供了分子解释。AP-2α是BCOR的抑制性靶点，BCOR突变导致AP-2α异常激活。功能获得和丧失测定表明AP-2α是介导MSC成骨/牙本质能力增加的关键因素。此外，我们发现BCOR通过表观遗传机制维持组织稳态和基因沉默。BCOR突变增加了MSC中组蛋白H3 K4/36甲基化，从而重新激活沉默的靶基因的转录。总之，通过研究一种罕见的人类遗传疾病，我们揭示了控制人类成体干细胞功能的表观遗传机制。
BCOR (BCL6 co-repressor) represses gene transcription by interacting with BCL-6. BCOR mutation is responsible for oculo-facio-cardio-dental (OFCD) syndrome, characterized by canine teeth with extremely long roots, congenital cataracts, craniofacial defects and congenital heart disease. Here we show that BCOR mutation increased osteo/dentinogenic potentials of mesenchymal stem cells (MSCs) isolated from an OFCD patient, providing a molecular explanation for abnormal root growth. AP-2α was identified as a repressive target of BCOR, and BCOR mutation resulted in abnormal activation of AP-2α. Gain- and loss-of-function assays suggested that AP-2α was a key factor that mediated increased osteo/dentinogenic capacity of MSCs. Moreover, we found that BCOR maintained tissue homeostasis and gene silencing by epigenetic mechanisms. BCOR mutation increased histone H3K4/36 methylation in MSCs, thereby reactivating transcription of silenced target genes. In summary, by studying a rare human genetic disease, we unravel an epigenetic mechanism for control of human adult stem cell function.
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