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Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

ABSTRACT: Tuberous Sclerosis Complex (TSC) is a rare genetic disorder that results from a mutation in the TSC1 or TSC2 genes leading to constitutive activation of the mechanistic target of rapamycin complex 1 (mTORC1). TSC is associated with autism, intellectual disability and severe epilepsy. Cortical tubers are believed to represent the neuropathological substrates of these disabling manifestations in TSC. In the presented study we used high-throughput RNA sequencing in combination with systems-based computational approaches to investigate the complexity of the TSC molecular network. Overall we detected 438 differentially expressed genes and 991 differentially expressed small non-coding RNAs in cortical tubers compared to autopsy control brain tissue. We observed increased expression of genes associated with inflammatory, innate and adaptive immune responses. In contrast, we observed a down-regulation of genes associated with neurogenesis and glutamate receptor signaling. MicroRNAs represented the largest class of over-expressed small non-coding RNA species in tubers. In particular, our analysis revealed that the miR-34 family (including miR-34a, miR-34b and miR-34c) was significantly over-expressed. Functional studies demonstrated the ability of miR-34b to modulate neurite outgrowth in mouse primary hippocampal neuronal cultures. This study provides new insights into the TSC transcriptomic network along with the identification of potential new treatment targets.

PROVIDER: EGAS00001002485 | EGA |

REPOSITORIES: EGA

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Project description:Background: Chronic spinal cord injury (SCI) remains one of the most debilitating neurological disorders and the majority of SCI patients are in the chronic phase. Previous studies of SCI that were limited by resources and technology have usually focused on few genes and pathways at a time. Thus, a comprehensive view of the complex molecular changes underlying SCI pathophysiology is needed. In particular, the biological roles of long non-coding RNAs (lncRNAs), a class of regulatory RNAs, have never been characterized systemically in SCI. Results: This study is the first to investigate alterations in the expression of both coding and long non-coding genes in the sub-chronic and chronic stages of SCI using RNA-Sequencing. Our data revealed differentially expressed genes, canonical pathways, and networks unique to particular time points or common to multiple time points in the progression of SCI. For example, a network of multiple critical genes responsible for astrogliosis and fibrosis was identified among differentially expressed genes common to three time points (1month, 3months, and 6 months after SCI). Moreover, the potential functions of rat lncRNAs in SCI were extensively analyzed. First, a comprehensive annotation database was compiled for rat lncRNAs that revealed several interesting characteristics of lncRNAs in the rat genome. Then, by correlating the temporal expression patterns of lncRNAs with those of protein-coding genes, we identified lncRNAs that are associated with functional categories such as signaling pathways, immune response, epigenetic modification, nervous system, and extracellular matrix. The expression patterns of some lncRNAs are highly correlated with those of their most proximal protein-coding genes, so it is possible that these lncRNAs regulate the expression of their protein-coding neighbors. Finally, we searched for transcription factor motifs enriched in the upstream regulatory regions of differentially expressed lncRNAs, and identified differentially expressed lncRNAs that are homologous to human genomic regions harboring molecular variants associated with human neurological diseases. Conclusions: Overall, our study provides an unprecedented resource for the study of sub-chronic and chronic SCI that will help the research community identify new molecular targets for future functional investigation.

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Coding and small non-coding transcriptional landscape of tuberous sclerosis complex cortical tubers: implications for pathophysiology and treatment

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