The IGF2BP family of RNA binding proteins links epitranscriptomics to cancer.

RNA binding proteins that act at the post-transcriptional level display a richness of mechanisms to modulate the transcriptional output and respond to changing cellular conditions. The family of IGF2BP proteins recognize mRNAs modified by methylation and lengthen their lifecycle in the context of stable ribonucleoprotein particles to promote cancer progression. They are emerging as key 'reader' proteins in the epitranscriptomic field, driving the fate of bound substrates under physiological and disease conditions. Recent developments in the field include the recognition that noncoding substrates play crucial roles in mediating the pro-growth features of IGF2BP family, not only as regulated targets, but also as modulators of IGF2BP function themselves. In this review, we summarize the regulatory roles of IGF2BP proteins and link their molecular role as m6A modification readers to the cellular phenotype, thus providing a comprehensive insight into IGF2BP function.

Analysis of the circRNA and T-UCR populations identifies convergent pathways in mouse and human models of Rett syndrome.

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.