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Mosca, R.

Publications and source records attributed to Mosca, R..

2 recordsLinked to original sources

Comprehensive analysis of the RBP regulome reveals functional modules and drug candidates in liver cancer

RNA binding proteins (RBPs) are essential components of the transcriptomic regulome. Identifying the RBP regulome in cancer cells is crucial to discovering and understanding carcinogenesis mechanisms and providing new therapeutic targets. Here, we aimed to reveal the regulome of liver cancer upon specific perturbations. To this end, we applied a consensus Gene Regulatory Network (GRN) approach using knockdown data for the liver cancer cell line HepG2. By incorporating multiple GRNs from diverse inference methods, we constructed a highly precise GRN. To validate our results, we comprehensively evaluated the consensus GRN, focusing on characterizing the most relevant aspects of the liver cancer regulome. This included utilizing eCLIP-seq and RAPseq data to verify RBP interactions and binding sites. In addition, we performed an enrichment analysis of network modules and drug repurposing based on the inferred GRN. Taken together, our findings demonstrate the critical roles of RBP regulatory interactions in liver cancer that can be employed to improve treatment strategies.

cancer biology↗

Truncating Variant Burden in High Functioning Autism and Pleiotropic Effects of LRP1 Across Psychiatric Phenotypes

Previous research has implicated de novo (DN) and inherited truncating mutations in autism spectrum disorder (ASD). We aim to investigate whether the load of inherited truncating mutations contribute similarly to high functioning autism (HFA), and to characterise genes harbouring DN variants in HFA.\n\nWe performed whole-exome sequencing (WES) in 20 HFA families (average IQ = 100). No difference was observed in the number of transmitted versus non-transmitted truncating alleles to HFA (117 vs 130, P = 0.32). Transmitted truncating and DN variants in HFA were not enriched in GO or KEGG categories, nor autism-related gene sets. However, in a HFA patient we identified a DN variant in a canonical splice site of LRP1, a post-synaptic density gene that is a target for the FMRP. This DN leads to in-frame skipping of exon-29, removing 2 of 6 blades of the {beta}-propeller domain-4 of LRP1, with putative functional consequences. Results using large datasets implicate LRP1 across psychiatric diseases: i) DN are associated with ASD (P = 0.039) and schizophrenia (P = 0.008) from combined sequencing projects; ii) Common variants using Psychiatric Genomics Consortium GWAS datasets show gene-based association in schizophrenia (P = 6.6E-07) and across six psychiatric diseases (meta-analysis P = 8.1E-05); and iii) burden of ultra-rare pathogenic variants is higher in ASD (P = 1.2E-05), using WES from 6,135 schizophrenia patients, 1,778 ASD patients and 6,245 controls. Previous and current studies suggest an impact of truncating mutations restricted to severe ASD phenotypes associated with intellectual disability. We provide evidence for pleiotropic effects of common and rare variants in the LRP1 gene across psychiatric phenotypes.

genomics↗