title: 'See-saw' expression of microRNA-198 and FSTL1 from a single transcript in wound healing.
abstract: Post-transcriptional switches are flexible effectors of dynamic changes in gene expression. 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), located in the 3'-untranslated region of follistatin-like 1 (FSTL1) 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 importance of this regulatory switch in controlling context-specific gene expression to orchestrate wound re-epithelialization. The deleterious effect of failure of this switch is apparent in non-healing chronic diabetic ulcers, in which expression of miR-198 persists, FSTL1 is absent, and keratinocyte migration, re-epithelialization and wound healing all fail to occur.
authors: Institute of Medical Biology, Agency for Science Technology & Research (A*STAR), 138648, Singapore.
authors: Gopinath M
authors: GM
authors: Sundaram
authors: John E A
authors: JE
authors: Common
authors: Felicia E
authors: FE
authors: Gopal
authors: Satyanarayana
authors: S
authors: Srikanta
authors: Krishnaswamy
authors: K
authors: Lakshman
authors: Declan P
authors: DP
authors: Lunny
authors: Thiam C
authors: TC
authors: Lim
authors: Vivek
authors: V
authors: Tanavde
authors: E Birgitte
authors: EB
authors: Lane
authors: Prabha
authors: P
authors: Sampath
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000378:metabolism; D002465:Cell Movement; D017719:Diabetic Foot / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005091:Exons / Q000235:genetics; D038702:Follistatin-Related Proteins / Q000096:biosynthesis / Q000235:genetics*; D000080865:Formins; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D066298:In Vitro Techniques; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D007797:Laminin / Q000037:antagonists & inhibitors / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D014945:Wound Healing / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C108962:DIAPH1 protein, human; D038702:Follistatin-Related Proteins; D000080865:Formins; C105789:KHSRP protein, human; C400567:LAMC2 protein, human; D007797:Laminin; C535221:MIRN198 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; C448799:FSTL1 protein, human; D014568:Urokinase-Type Plasminogen Activator
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