Orchestrated Intron Retention Regulates Normal Granulocyte Differentiation

• Published in: Cell 2013-08, Vol.154 (3), p.583-595
• Main Authors: Wong, Justin J.-L., Ritchie, William, Ebner, Olivia A., Selbach, Matthias, Wong, Jason W.H., Huang, Yizhou, Gao, Dadi, Pinello, Natalia, Gonzalez, Maria, Baidya, Kinsha, Thoeng, Annora, Khoo, Teh-Liane, Bailey, Charles G., Holst, Jeff, Rasko, John E.J.
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Base Composition; bioinformatics; cell differentiation; Cell Nucleus - metabolism; Down-Regulation; excision; gene expression; gene expression regulation; genes; granulocytes; Granulocytes - cytology; Granulocytes - metabolism; Hematopoiesis; Humans; Introns; Lamin Type B - genetics; messenger RNA; Mice; Mice, Inbred C57BL; Nonsense Mediated mRNA Decay; proteins; proteomics; RNA Splicing; transcriptomics; translation (genetics)
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.06.052

Intron retention (IR) is widely recognized as a consequence of mis-splicing that leads to failed excision of intronic sequences from pre-messenger RNAs. Our bioinformatic analyses of transcriptomic and proteomic data of normal white blood cell differentiation reveal IR as a physiological mechanism of gene expression control. IR regulates the expression of 86 functionally related genes, including those that determine the nuclear shape that is unique to granulocytes. Retention of introns in specific genes is associated with downregulation of splicing factors and higher GC content. IR, conserved between human and mouse, led to reduced mRNA and protein levels by triggering the nonsense-mediated decay (NMD) pathway. In contrast to the prevalent view that NMD is limited to mRNAs encoding aberrant proteins, our data establish that IR coupled with NMD is a conserved mechanism in normal granulopoiesis. Physiological IR may provide an energetically favorable level of dynamic gene expression control prior to sustained gene translation. [Display omitted] •Conserved intron retention (IR) affects 86 genes during granulopoiesis•IR is linked to reduced splicing factor levels and increased intronic GC content•IR triggers nonsense-mediated decay that reduces protein expression•Preventing IR in Lmnb1 reduces granulocyte numbers and alters nuclear volume Intron retention coupled to nonsense-mediated decay is important not only for the clearance of aberrant transcripts, but also as a conserved regulatory mechanism limiting the expression of dozens of normal genes during granulocyte differentiation.