‘See-saw’ expression of microRNA-198 and FSTL1 from a single transcript in wound healing

• Published in: Nature (London) 2013-03, Vol.495 (7439), p.103-106
• Main Authors: Sundaram, Gopinath M., Common, John E. A., Gopal, Felicia E., Srikanta, Satyanarayana, Lakshman, Krishnaswamy, Lunny, Declan P., Lim, Thiam C., Tanavde, Vivek, Lane, E. Birgitte, Sampath, Prabha
• Format: Article
• Language: English
• Subjects: 631/337/384/331; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - metabolism; Binding proteins; Binding sites; Cell adhesion & migration; Cell Movement; Diabetes; Diabetic Foot - genetics; Diabetic Foot - metabolism; Diabetic Foot - pathology; Exons - genetics; Follistatin-Related Proteins - biosynthesis; Follistatin-Related Proteins - genetics; Gene expression; Gene Expression Regulation - genetics; Genetic transcription; Humanities and Social Sciences; Humans; In Vitro Techniques; Keratinocytes - cytology; Keratinocytes - metabolism; Laminin - antagonists & inhibitors; Laminin - metabolism; letter; Messenger RNA; MicroRNA; MicroRNAs - genetics; multidisciplinary; Open Reading Frames - genetics; Properties; Proteins; RNA, Messenger - genetics; RNA-Binding Proteins - genetics; RNA-Binding Proteins - metabolism; Science; Skin; Skin - cytology; Skin - injuries; Skin - metabolism; Skin - pathology; Time Factors; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription, Genetic - genetics; Transforming Growth Factor beta1 - metabolism; Urokinase-Type Plasminogen Activator - antagonists & inhibitors; Urokinase-Type Plasminogen Activator - metabolism; Wound healing; Wound Healing - genetics
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11890

A post-transcriptional switch that controls spatiotemporal and mutually exclusive expression of two alternative gene products from a single transcript is reported; these gene products—miR-198 and FSTL1—are found to have opposing functions on keratinocyte migration and wound healing. Pivotal point in wound healing Wound healing is a complicated process involving coordinated cell migration, cell proliferation and extracellular matrix remodelling in response to TGF-β and other growth factors. Prabha Sampath and colleagues report a post-transcriptional switch that controls spatiotemporal and mutually exclusive expression of two alternative gene products from a single transcript. The two have opposing effects: the secreted glycoprotein FSTL1 is necessary for wound healing and the microRNA miR-198 suppresses keratinocyte migration and is essential for epidermal homeostasis in healthy skin. In normal keratinocytes, miR-198 is predominantly expressed from the dual transcript and it in turn attenuates several keratinocyte migrating genes. After injury, TGF-β signalling switches off miR-198 expression by downregulating the RNA-binding protein KSRP, thereby promoting FSTL1 protein expression. The findings may be relevant to the pathology of chronic diabetic ulcers, in which expression of miR-198 persists. Post-transcriptional switches are flexible effectors of dynamic changes in gene expression 1 . Here we report a new post-transcriptional switch that dictates the spatiotemporal and mutually exclusive expression of two alternative gene products from a single transcript. Expression of primate-specific exonic microRNA-198 (miR-198) 2 , located in the 3′-untranslated region of follistatin-like 1 ( FSTL1 ) 3 messenger RNA, switches to expression of the linked open reading frame of FSTL1 upon wounding in a human ex vivo organ culture system. We show that binding of a KH-type splicing regulatory protein (KSRP, also known as KHSRP) to the primary transcript determines the fate of the transcript and is essential for the processing of miR-198: transforming growth factor-β signalling switches off miR-198 expression by downregulating KSRP, and promotes FSTL1 protein expression. We also show that FSTL1 expression promotes keratinocyte migration, whereas miR-198 expression has the opposite effect by targeting and inhibiting DIAPH1 , PLAU and LAMC2 . A clear inverse correlation between the expression pattern of FSTL1 (pro-migratory) and miR-198 (anti-migratory) highlights the impo