The Regulatory Landscape of Osteogenic Differentiation
The Regulatory Landscape of Osteogenic Differentiation
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DOI：
10.1002/stem.1759
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发表时间：
2014-10-01
期刊：
影响因子：
5.2
通讯作者：
Meza-Zepeda, Leonardo A.
中科院分区：
文献类型：
--
作者：
Hakelien, Anne-Mari;Bryne, Jan Christian;Meza-Zepeda, Leonardo A.
从间充质干细胞(MSCs)向成骨细胞分化是骨发育和内环境稳定的重要组成部分，如果调控不当，可能会导致骨癌或骨质疏松等疾病。使用无偏见的高通量方法，我们在这里描述了当人MSCs分化为成骨细胞时，基因表达、组蛋白修饰和DNA甲基化的全球变化的图景。此外，我们首次在全基因组范围内鉴定了人类成骨细胞中骨主转录因子Run-Related转录因子2(RUNX2)的DNA结合位点，揭示了与增殖、迁移、凋亡调控相关的靶基因，并与P53调控的基因显著重叠。这些发现扩大了RUNX2在癌症(包括骨转移)和p53调控网络中发挥作用的新证据。我们进一步证明RUNX2与遥远的调控元件、启动子结合，并且与基因30末端结合的频率很高。最后，我们确定TEAD2和GTF2I是新的成骨调节因子。
Differentiation of osteoblasts from mesenchymal stem cells (MSCs) is an integral part of bone development and homeostasis, and may when improperly regulated cause disease such as bone cancer or osteoporosis. Using unbiased high-throughput methods we here characterize the landscape of global changes in gene expression, histone modifications, and DNA methylation upon differentiation of human MSCs to the osteogenic lineage. Furthermore, we provide a first genome-wide characterization of DNA binding sites of the bone master regulatory transcription factor Runt-related transcription factor 2 (RUNX2) in human osteoblasts, revealing target genes associated with regulation of proliferation, migration, apoptosis, and with a significant overlap with p53 regulated genes. These findings expand on emerging evidence of a role for RUNX2 in cancer, including bone metastases, and the p53 regulatory network. We further demonstrate that RUNX2 binds to distant regulatory elements, promoters, and with high frequency to gene 30 ends. Finally, we identify TEAD2 and GTF2I as novel regulators of osteogenesis.