The mechanisms used by antisense transcripts to regulate their corresponding sense mRNAs are not fully understood. Herein, we have addressed this issue for the vimentin (VIM) gene, a member of the intermediate filament family involved in cell and tissue integrity that is deregulated in different types of cancer. VIM mRNA levels are positively correlated with the expression of a previously uncharacterized head-to-head antisense transcript, both transcripts being silenced in colon primary tumors concomitant with promoter hypermethylation. Furthermore, antisense transcription promotes formation of an R-loop structure that can be disfavored in vitro and in vivo by ribonuclease H1 overexpression, resulting in VIM downregulation. Antisense knockdown and R-loop destabilization both result in chromatin compaction around the VIM promoter and a reduction in the binding of transcriptional activators of the NF-κB pathway. These results are the first examples to our knowledge of R-loop-mediated enhancement of gene expression involving head-to-head antisense transcription at a cancer-related locus.

One largely unknown question in cell biology is the discrimination between inconsequential and functional transcriptional events with relevant regulatory functions. Here, we find that the oncofetal HMGA2 gene is aberrantly reexpressed in many tumor types together with its antisense transcribed pseudogene RPSAP52 . RPSAP52 is abundantly present in the cytoplasm, where it interacts with the RNA binding protein IGF2BP2/IMP2, facilitating its binding to mRNA targets, promoting their translation by mediating their recruitment on polysomes and enhancing proliferative and self-renewal pathways. Notably, downregulation of RPSAP52 impairs the balance between the oncogene LIN28B and the tumor suppressor let-7 family of miRNAs, inhibits cellular proliferation and migration in vitro and slows down tumor growth in vivo. In addition, high levels of RPSAP52 in patient samples associate with a worse prognosis in sarcomas. Overall, we reveal the roles of a transcribed pseudogene that may display properties of an oncofetal master regulator in human cancers.

Noncoding RNAs play regulatory roles in physiopathology, but their involvement in neurodevelopmental diseases is poorly understood. Rett syndrome is a severe, progressive neurodevelopmental disorder linked to loss-of-function mutations of the MeCP2 gene for which no cure is yet available. Analysis of the noncoding RNA profile corresponding to the brain-abundant circular RNA (circRNA) and transcribed-ultraconserved region (T-UCR) populations in a mouse model of the disease reveals widespread dysregulation and enrichment in glutamatergic excitatory signaling and microtubule cytoskeleton pathways of the corresponding host genes. Proteomic analysis of hippocampal samples from affected individuals confirms abnormal levels of several cytoskeleton-related proteins together with key alterations in neurotransmission. Importantly, the glutamate receptor GRIA3 gene displays altered biogenesis in affected individuals and in vitro human cells and is influenced by expression of two ultraconserved RNAs. We also describe post-transcriptional regulation of SIRT2 by circRNAs, which modulates acetylation and total protein levels of GluR-1. As a consequence, both regulatory mechanisms converge on the biogenesis of AMPA receptors, with an effect on neuronal differentiation. In both cases, the noncoding RNAs antagonize MeCP2-directed regulation. Our findings indicate that noncoding transcripts may contribute to key alterations in Rett syndrome and are not only useful tools for revealing dysregulated processes but also molecules of biomarker value.

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An increasing amount of evidence points to key roles for noncoding RNAs in gene expression regulation and cell function. Similar to smaller species, long noncoding RNAs (lncRNAs) are involved in a myriad of molecular pathways, impacting on and fine-tuning proliferative and differentiating cellular programs. Specifically in tumorigenesis, several lncRNAs have been shown to display growth enhancing or arrest properties and can therefore be considered as true oncogenes or tumor suppressor genes. This review focuses on the latest findings in the noncoding field regarding transcripts with crucial roles in proliferative signaling.

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