Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Int J Mol Sci. 2023 Feb 3;24(3):2979. doi: 10.3390/ijms24032979.
Skeletal development is tightly coordinated by chondrocytes and osteoblasts, which are derived from skeletal progenitors, and distinct cell-type gene regulatory programs underlie the specification and differentiation of cells. Runt-related transcription factor 2 (Runx2) is essential to chondrocyte hypertrophy and osteoblast differentiation. Genetic studies have revealed the biological functions of and its involvement in skeletal genetic diseases. Meanwhile, molecular biology has provided a framework for our understanding of RUNX2-mediated transactivation at a limited number of cis-regulatory elements. Furthermore, studies using next-generation sequencing (NGS) have provided information on RUNX2-mediated gene regulation at the genome level and novel insights into the multiple layers of gene regulatory mechanisms, including the modes of action of RUNX2, chromatin accessibility, the concept of pioneer factors and phase separation, and three-dimensional chromatin organization. In this review, I summarize the emerging RUNX2-mediated regulatory mechanism from a multi-layer perspective and discuss future perspectives for applications in the treatment of skeletal diseases.
骨骼发育是由软骨细胞和成骨细胞紧密协调的，软骨细胞和成骨细胞来源于骨骼祖细胞，而不同的细胞类型基因调控程序则是细胞特化和分化的基础。 runt 相关转录因子 2（Runx2）对于软骨细胞肥大和成骨细胞分化是必不可少的。遗传研究揭示了 的生物学功能及其在骨骼遗传疾病中的作用。同时，分子生物学为我们理解有限数量的顺式调控元件中 RUNX2 介导的转录激活提供了一个框架。此外，使用下一代测序（NGS）的研究提供了关于 RUNX2 介导的基因组水平基因调控的信息，并为基因调控机制的多个层次提供了新的见解，包括 RUNX2 的作用模式、染色质可及性、先驱因子和相分离的概念以及三维染色质组织。在这篇综述中，我从多层次的角度总结了新兴的 RUNX2 介导的调控机制，并讨论了在骨骼疾病治疗中的应用的未来展望。
