‘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.

Downregulation of miRNAs during Delayed Wound Healing in Diabetes: Role of Dicer

“…miRNAs have been identified to be critical in wound healing (24,(36)(37)(38). Our results demonstrate an inhibited miRNA signature in the wounds of diabetic rats accompanied by decreased Dicer levels.…”

“…In type 2 diabetic KKAy mice, 14 miRNAs were differentially regulated in the wounded skin, and miR-21 was identified to be critical in fibroblast migration (23). In chronic nonhealing diabetic ulcers, persistent elevated miR-198 expression impairs keratinocyte mig ration and reepithelialization, thereby delaying wound closure (24). Except for these sparse reports, not much has been reported on the roles and mechanisms of miRNAs in delayed wound healing during diabetes.…”

Most microRNAs in the single-cell alga Chlamydomonas reinhardtii are produced by Dicer-like 3-mediated cleavage of introns and untranslated regions of coding RNAs

“…The mRNAs with miRNA structures in the UTR overaccumulated in the dcl3 mutants, indicating that they are targeted for degradation by DCL3 in wild-type cells (Supplemental Table S3). An equivalent mechanism occurs with the mammalian FSTL1 mRNA that is destabilized by Drosha during hs-miR198 biogenesis (Sundaram et al 2013). Similarly the DGCR8 mRNA is destabilized by Drosha cleavage via cleavage of a hairpin-like structure at the 3 ′ UTR, although there is no miRNA produced ).…”

miR-198 functions as a tumor suppressor in breast cancer by targeting CUB domain-containing protein 1

“…Thus, the miRNA/target link in certain cancers may shed light on the molecular mechanism underlying cancer progression and provide useful potential therapeutic targets for the clinical treatment of certain cancers. miR-198 was reported to be located in the 3'UTR of follistatin-like 1 messenger RNA, which promotes keratinocyte migration, whereas miR-198 expression has the opposite effect (24). In human cancers, miR-198 was reported to be downregulated in colorectal (4), lung (5), pancreatic (6) and hepatocellular carcinoma (8,9), and generally acts as a tumor suppressor by inhibiting cancer cell growth and migration.…”