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The deletion of the Williams-Beuren Syndrome critical region dysregulate the expression of miR379-410 miRNA members in human isogenic iNeurons

ABSTRACT: While psychiatric disorders (e.g., schizophrenia) and autism spectrum disorders (ASD) are typically associated with a deficit in social behavior, the opposite trait of hypersociability is exhibited by individuals with specific neurodevelopmental disorders, e.g., Angelman Syndrome (AS) and Williams-Beuren Syndrome (WBS). We have recently reported that the deletion of the miR379-410 cluster in mice led to hypersocial behavior. To study the roles of this miRNA cluster in the context of WBS, we sent for smallRNA sequencing RNA isolated from isogenic human iPSC-derived neurons harboring a deletion present in Williams-Beuren-Syndrome patients (7q11.23). Specifically, we found that members of the miR379-410 cluster were strikingly overrepresented among downregulated miRNAs in iNeurons harboring a deletion of the WBS critical region. Thus, we obtained the first evidence for the pathophysiological significance of the miR379-410 miRNA cluster in the context of WBS. We conclude that targeting this novel pathway could have therapeutic potential for WBS and other neurodevelopmental conditions characterized by social impairments.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247766 | GEO | 2023/11/15

REPOSITORIES: GEO

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Project description:We apply the cellular reprogramming experimental paradigm to two disorders caused by symmetrical copy number variations (CNV) of 7q11.23 and displaying a striking combination of shared as well as symmetrically opposite phenotypes: Williams Beuren syndrome (WBS) and 7q microduplication syndrome (7dupASD). Through a uniquely large and informative cohort of transgene-free patient-derived induced pluripotent stem cells (iPSC), along with their differentiated derivatives, we find that 7q11.23 CNV disrupt transcriptional circuits in disease-relevant pathways already at the pluripotent state. These alterations are then selectively amplified upon differentiation into disease-relevant lineages, thereby establishing the value of large iPSC cohorts in the elucidation of disease-relevant developmental pathways. In addition, we functionally define the quota of transcriptional dysregulation specifically caused by dosage imbalances in GTF2I (also known as TFII-I), a transcription factor in 7q11.23 thought to play a critical role in the two conditions, which we found associated to key repressive chromatin modifiers. Finally, we created an open-access web-based platform (accessible at http://bio.ieo.eu/wbs/ ) to make accessible our multi-layered datasets and integrate contributions by the entire community working on the molecular dissection of the 7q11.23 syndromes. We reprogrammed skin fibroblasts from patients harbouring a 7q11.23 hemi-deletion (WBS, 4 patients; +1 atypical deletion, AtWBS) or microduplication (7dupASD; 2 patients), as well as from one unaffected relative and two unrelated controls, using integration-free mRNA-reprogramming, leading to the establishment of a total of 27 characterized iPSC clones. We profiled these by RNAseq (either polyA or ribo-zero). To isolate the contribution of GTF2I to the transcriptional dysregulation, we created stable lines expressing a short hairpin against GTF2I from a representative subset of these iPSC clones, and profiled by RNAseq 7 such lines along with their respective scramble controls. Finally, we also profiled by RNAseq mesenchymal stem cells (MSC) derived from a representative subset of the lines.

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The deletion of the Williams-Beuren Syndrome critical region dysregulate the expression of miR379-410 miRNA members in human isogenic iNeurons

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