Cellular quiescence and cell cycle re-entry regulate vital biological processes such as cellular development and tissue homeostasis, and are controlled by precise regulation of gene expression. The roles of long noncoding RNAs (lncRNAs) during these processes remain to be elucidated. By performing genome-wide transcriptome analyses, we identify differential expression of several hundreds of lncRNAs, including a significant number of the less-characterized class of microRNA-host-gene (MIRHG) lncRNAs or lnc-MIRHGs, during cellular quiescence and cell cycle re-entry in human diploid fibroblasts. We observe that MIR222HG lncRNA displays serum-stimulated RNA processing due to enhanced splicing of the host nascent pri-MIR222HG transcript. The pre-mRNA splicing factor SRSF1 negatively regulates the microprocessor-catalyzed cleavage of pri-miR-222, thereby increasing the cellular pool of the mature MIR222HG. Association of SRSF1 to pri-MIR222HG, including to a mini-exon, which partially overlaps with the primary miR-222 precursor, promotes serum-stimulated splicing over microRNA processing of MIR222HG. Further, we observe that the increased levels of spliced MIR222HG in serum-stimulated cells promote the cell cycle re-entry post quiescence in a microRNA-independent manner. MIR222HG interacts with DNM3OS, another lncRNA whose expression is elevated upon serum-stimulation and promotes cell cycle re-entry. The double-strand RNA binding protein ILF3/2 complex facilitates MIR222HG:DNM3OS RNP complex assembly, thereby promoting DNM3OS RNA stability. Our study identifies a novel mechanism whereby competition between the splicing and microprocesser machinery modulates the serum-induced RNA processing of MIR222HG, which dictates cell cycle re-entry.

中文翻译：

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剪接和微处理器复合物之间的拮抗作用决定了 Lnc-MIRHG 的血清诱导处理以实现有效的细胞周期再进入

细胞静止和细胞周期重新进入调节重要的生物过程，如细胞发育和组织稳态，并受基因表达的精确调节控制。长链非编码 RNA (lncRNA) 在这些过程中的作用仍有待阐明。通过进行全基因组转录组分析，我们确定了数百种 lncRNA 的差异表达，包括大量特征较少的 microRNA 宿主基因 (MIRHG) lncRNA 或 lnc-MIRHG，在细胞静止和细胞周期恢复期间。 -进入人二倍体成纤维细胞。我们观察到，由于宿主新生 pri-MIR222HG 转录本的剪接增强，MIR222HG lncRNA 显示出血清刺激的 RNA 加工。前体 mRNA 剪接因子 SRSF1 负向调节微处理器催化的 pri-miR-222 裂解，从而增加成熟 MIR222HG 的细胞库。SRSF1 与 pri-MIR222HG 的关联，包括与主要 miR-222 前体部分重叠的小外显子，促进血清刺激的剪接超过 MIR222HG 的 microRNA 加工。此外，我们观察到血清刺激细胞中剪接 MIR222HG 水平的增加以一种不依赖微小 RNA 的方式促进细胞周期在静止后重新进入。MIR222HG 与 DNM3OS 相互作用，DNM3OS 是另一种 lncRNA，其表达在血清刺激时升高并促进细胞周期重新进入。双链 RNA 结合蛋白 ILF3/2 复合物促进 MIR222HG:DNM3OS RNP 复合物组装，从而促进 DNM3OS RNA 稳定性。