Department of Ultrasound Imaging, Renmin Hospital of Wuhan University, Hubei, Wuhan, People's Republic of China.
Department of Orthopedics, Renmin Hospital of Wuhan University, Hubei, Wuhan, People's Republic of China.
BMC Genomics. 2024 Apr 5;25(1):345. doi: 10.1186/s12864-024-10204-6.
High-mobility group B1 (HMGB1) is both a DNA binding nuclear factor modulating transcription and a crucial cytokine that mediates the response to both infectious and noninfectious inflammation such as autoimmunity, cancer, trauma, and ischemia reperfusion injury. HMGB1 has been proposed to control ribosome biogenesis, similar as the other members of a class of HMGB proteins.
Here, we report that HMGB1 selectively promotes transcription of genes involved in the regulation of transcription, osteoclast differentiation and apoptotic process. Improved RNA immunoprecipitation by UV cross-linking and deep sequencing (iRIP-seq) experiment revealed that HMGB1 selectively bound to mRNAs functioning not only in signal transduction and gene expression, but also in axon guidance, focal adhesion, and extracellular matrix organization. Importantly, HMGB1-bound reads were strongly enriched in specific structured RNAs, including the domain II of 28S rRNA, H/ACA box snoRNAs including snoRNA63 and scaRNAs. RTL-P experiment showed that overexpression of HMGB1 led to a decreased methylation modification of 28S rRNA at position Am2388, Cm2409, and Gm2411. We further showed that HMGB1 overexpression increased ribosome RNA expression levels and enhanced protein synthesis.
Taken together, our results support a model in which HMGB1 binds to multiple RNA species in human cancer cells, which could at least partially contribute to HMGB1-modulated rRNA modification, protein synthesis function of ribosomes, and differential gene expression including rRNA genes. These findings provide additional mechanistic clues to HMGB1 functions in cancers and cell differentiation.
高迁移率族蛋白 B1（HMGB1）既是一种调节转录的 DNA 结合核因子，也是一种关键细胞因子，介导对感染和非感染性炎症（如自身免疫、癌症、创伤和缺血再灌注损伤）的反应。HMGB1 被提议控制核糖体生物发生，类似于其他 HMGB 蛋白家族成员。
在这里，我们报告 HMGB1 选择性地促进参与转录、破骨细胞分化和凋亡过程调节的基因的转录。通过紫外线交联和深度测序（iRIP-seq）实验改进的 RNA 免疫沉淀显示，HMGB1 选择性地结合到不仅在信号转导和基因表达中起作用，而且在轴突导向、焦点粘附和细胞外基质组织中起作用的 mRNA。重要的是，HMGB1 结合的读数强烈富集在特定的结构化 RNA 中，包括 28S rRNA 的结构域 II、包含 snoRNA63 和 scaRNAs 的 H/ACA 盒 snoRNA。RTL-P 实验表明，HMGB1 的过表达导致 28S rRNA 位置 Am2388、Cm2409 和 Gm2411 处的甲基化修饰减少。我们进一步表明，HMGB1 的过表达增加了核糖体 RNA 的表达水平并增强了蛋白质合成。
总之，我们的结果支持 HMGB1 结合人癌细胞中多种 RNA 物种的模型，这至少可以部分解释 HMGB1 调节 rRNA 修饰、核糖体 RNA 合成功能和包括 rRNA 基因在内的差异基因表达的作用。这些发现为 HMGB1 在癌症和细胞分化中的功能提供了额外的机制线索。
