Transcriptome analysis of iPSC-derived neurons from Rubinstein-Taybi patients reveals deficits in neuronal differentiation.

ABSTRACT: Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of either CREBBP or EP300 genes encoding CBP/p300 chromatin modifiers. We explored the gene programs and processes underlying the morphological and functional alterations shown by iPSC-derived neurons modeling RSTS to bridge the molecular changes resulting from defective CBP/p300 to cognitive impairment. By global transcriptome analysis we compared the differentially expressed genes (DEGs) marking the transition from iPSC-derived neural progenitors to cortical neurons (iNeurons) of five RSTS patients carrying private CREBBP/EP300 mutations manifesting differently graded neurocognitive signs with those of four healthy controls. Our data shows a defective and altered neuroprogenitor to neuron transcriptional program in the cells from RSTS patients as compared to controls. First, transcriptional regulation is weaker in RSTS as less genes than in controls are modulated, including genes of key processes of mature functional neurons, such as those involved in synaptic integration. Second, regulation is subverted as genes acting at pre-terminal stages of neural differentiation in cell polarity and adhesive functions (members of the cadherin family) and axon extension/guidance (members of the semaphorins and SLIT receptors families) are improperly upregulated. Impairment or delay of RSTS neuronal differentiation program is also evidenced by decreased modulation of the overall number of neural differentiation markers, significantly impacting the initial and final stages of the differentiation cascade. Last, extensive downregulation of genes for RNA/DNA metabolic processes confirms that RSTS is a global transcription disorder, consistent with a syndrome driven by chromatin dysregulation. Interestingly, the overall transcriptome changes validate the morphological and functional alterations previously appointed as biomarkers of RSTS iNeurons, accounting for patients’ cognitive deficit. The impact of RSTS transcriptome may go beyond RSTS as cross-comparison of dysregulated genes with other modeled neurodevelopmental disorders could enhance to unveil the core genes of cognitive impairment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135287 | GEO | 2020/06/24

REPOSITORIES: GEO