Chen Yuyu, Zhou Taifeng, Liao Zhiheng, Gao Wenjie, Wu Jinna, Zhang Shun, Li Yongyong, Liu Hengyu, Zhou Hang, Xu Caixia, Su Peiqiang
Department of Spine Surgery, Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China.
Department of Orthopaedics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510120, China.
Cell Death Differ. 2023 Oct;30(10):2293-2308. doi: 10.1038/s41418-023-01207-z. Epub 2023 Aug 22.
Proper development of the limb bud relies on the concordance of various signals, but its molecular mechanisms have not yet been fully illustrated. Here we report that heterogeneous nuclear ribonucleoprotein K (hnRNPK) is essential for limb bud development. Its ablation in the limb bud results in limbless forelimbs and severe deformities of the hindlimbs. In terms of mechanism, hnRNPK functions as a transcription activator for the vital genes involved in the three regulatory axes of limb bud development. Simultaneously, for the first time we elucidate that hnRNPK binds to and coordinates with the insulator protein CCCTC binding factor (CTCF) to maintain a three-dimensional chromatin architecture. Ablation of hnRNPK weakens the binding strength of CTCF to topologically associating domain (TAD) boundaries, then leading to the loose TADs, and decreased interactions between promoters and enhancers, and further decreased transcription of developmental genes. Our study establishes a fundamental and novel role of hnRNPK in regulating limb bud development.
肢体芽的正常发育依赖于多种信号的协同作用，但其分子机制尚未完全阐明。在此，我们报告异质性核糖核蛋白K（hnRNPK）对肢体芽发育至关重要。其在肢体芽中的缺失会导致前肢无肢以及后肢严重畸形。在机制方面，hnRNPK作为参与肢体芽发育三个调控轴的关键基因的转录激活因子发挥作用。同时，我们首次阐明hnRNPK与绝缘子蛋白CCCTC结合因子（CTCF）结合并协同作用，以维持三维染色质结构。hnRNPK的缺失会削弱CTCF与拓扑相关结构域（TAD）边界的结合强度，进而导致TAD松散，启动子与增强子之间的相互作用减少，以及发育基因的转录进一步降低。我们的研究确立了hnRNPK在调节肢体芽发育中的重要且新颖的作用。
