Biology subjects

Essafi, A.

Publications and source records attributed to Essafi, A..

3 recordsLinked to original sources

bioRxiv2025

Tumour suppressor WT1 and its interacting protein RNA helicase DDX5 regulate the microRNA let7/Igf1r axis in the kidney mesenchyme

Germline mutations in tumour suppressor, Wilms Tumour 1 (WT1) as well as somatic and germline mutations in microRNA processing genes (MIRPG) have been identified in Wilms Tumours (WT), where upregulation of IGF2 through genetic and/or epigenetic mechanisms is commonly seen. Whether these different epigenetic and genetic causes converge on common targets is still unclear. WT1 is also involved in RNA binding and regulates the stability of these developmental mRNAs. We now show that WT1 interacts with microRNA let-7 and proteins involved in microRNA processing wherein DDX5 is found to be an important regulator. WT1 absence results in decreased microRNA levels in cell lines and kidney mesenchyme, which is further downregulated in a WT1 and DDX5 double knockdown, ultimately modulating Igf1r expression. These findings suggest a plausible mechanism by which WT1 mutations lead to WT, and converge on microRNA pathway and IGF signalling pathway, which are important contributing factors in the aetiology of WT.

cancer biology↗

bioRxiv2019

Tumour suppressor WT1 regulates the let-7-Igf1r axis in kidney mesenchyme

Wilms tumour 1 (WT1) is a transcription factor and a tumour suppressor, essential for the development and homeostasis of multiple tissues derived from the intermediate and lateral plate mesoderm. Germline WT1 mutations result in the eponymous paediatric kidney cancer, genitourinary anomalies and in some cases congenital diaphragmatic hernia One common feature in Wilms Tumours (WT), is upregulation of IGF2 through genetic and/or epigenetic mechanisms. Recent studies have identified both somatic and germline mutations in microRNA processing genes (MIRPG) in WT. Whether these different epigenetic and genetic causes converge on common targets and the mechanisms by which they act are still unclear. WT1 is involved in RNA binding and regulates the RNA stability of important developmental genes. We now show that WT1 interacts with let-7 family of microRNAs, and the absence of WT1 results in reduced levels of mature microRNA in cell lines and kidney mesenchyme. As a consequence, let-7 targets, including Igf1 receptor (Igf1r), are upregulated in the absence of Wt1, thus confirming the presence of a WT1-let7-Igf1r axis. These findings suggest a possible mechanism by which WT1 mutations lead to WT, and reinforce the idea that the perturbation of the microRNA and IGF signalling pathways are important contributing factors in the aetiology of WT.

cancer biology↗

bioRxiv2018

Functionally Coherent Transcription Factor Target Networks Illuminate Control of Epithelial Remodelling and Oncogenic Notch

BackgroundCell identity is governed by gene expression, regulated by Transcription Factor (TF) binding at cis-regulatory modules. Decoding the relationship TF binding patterns and the regulation of cognate target genes is nontrivial, remaining a fundamental limitation in understanding cell decision-making mechanisms. Identification of TF physical binding that is biologically neutral is a current challenge. We studied cell identity in the context of Epithelial to Mesenchymal Transition (EMT), a cell programme fundamental for normal embryonic development that contributes to tumour progression and fibrosis.\n\nResultsWe developed the NetNC software for discovery of functionally coherent TF targets. NetNC was applied to analyse gene regulation by the EMT TFs Snail, Twist in early embryogenesis and also to modENCODE HOT regions. Predicted neutral binding accounted for 50% to [≥]80% of candidate target genes assigned from significant binding peaks. Novel gene functions and network modules were identified, including regulation of chromatin organisation and crosstalk with notch signalling. Orthologues of predicted TF targets discriminated breast cancer molecular subtypes and NetNC analysis predicted new gene functions; for example, evidencing networks that reshape Waddingtons landscape during EMT-like phenotype switching. Predicted invasion roles for SNX29, ATG3, UNK and IRX4 were validated using a tractable cell model.\n\nConclusionsWe found extensive neutral TF binding across the nine datasets examined and showed that NetNC performs well in identifying functionally coherent targets. HOT regions had comparatively high functional coherence. Our results illuminate conserved molecular networks that regulate epithelial remodelling in development and disease, with potential implications for precision medicine.

systems biology↗