Aberrant transcription regulation in a subset of individuals affected by Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) is a set of heterogeneous neurodevelopmental conditions mainly involving impaired communication and repetitive behaviors. It is known that genetics have a fundamental but yet not completely understood role in its etiology. Indeed, several hundreds genes have been implicated into ASD pathogenesis and susceptibility. Interestingly, not all these genes present a direct role in neuronal functions. Indeed ASD-related genes may be mainly divided into two categories: genes with a critical role in synaptic functions and genes involved in chromatin remodeling or regulation of transcription. The link between the latter and the neurological manifestations of ASD has not been uncovered yet. Starting from this insight I sought to stratify ASD cases into two experimental groups on the basis of the presence or absence of potentially deleterious mutations within ASD-related genes involved in transcriptional regulation and/or chromatin remodeling. I then explored the putatively different transcriptional landscape unique to each one of the two subset of patients in terms of gene and transposable elements expression. I detected a pervasive up-regulation of LINE transposable elements and down-regulation of genes important for synaptic functions only in the experimental group including ASD individuals carrying a putatively deleterious mutation within a regulatory gene. Interestingly, up-regulated LINEs are enriched within down-regulated genes. Furthermore I characterized the genomic location of DE non-coding genomic elements in order to try to reconstruct the regulatory alterations at the basis of the differential expression observed. Finally I replicated our experiments on independent datasets in order to test their reproducibility.