Transcriptome Analysis of iPSC-Derived Neurons from Rubinstein-Taybi Patients Reveals Deficits in Neuronal Differentiation
Por:
Calzari, L, Barcella, M, Alari, V, Braga, D, Munoz-Viana, R, Barlassina, C, Finelli, P, Gervasini, C, Barco, A, Russo, S and Larizza, L
Publicada:
1 sep 2020
Ahead of Print:
1 jun 2020
Resumen:
Rubinstein-Taybi syndrome (RSTS) is a rare multisystem developmental disorder with moderate to severe intellectual disability caused by heterozygous mutations of eitherCREBBPorEP300genes encoding CBP/p300 chromatin regulators. 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 privateCREBBP/EP300mutations and 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. 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 for voltage-gated channels and neurotransmitters and their receptors. 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 morphological and functional alterations we have previously appointed as biomarkers of RSTS iNeurons provide functional support to the herein designed transcriptome profile pointing to key dysregulated neuronal genes as main contributors to patients' cognitive deficit. The impact of RSTS transcriptome may go beyond RSTS as comparison of dysregulated genes across modeled neurodevelopmental disorders could unveil convergent genes of cognitive impairment.
Filiaciones:
Calzari, L:
IRCCS, Ist Auxol Italian, Cytogenet & Mol Genet Lab, Milan, Italy
Barcella, M:
Univ Milan, Dept Hlth Sci, Genom & Bioinformat Unit, Milan, Italy
Alari, V:
IRCCS, Ist Auxol Italian, Cytogenet & Mol Genet Lab, Milan, Italy
Braga, D:
Univ Milan, Dept Hlth Sci, Genom & Bioinformat Unit, Milan, Italy
Munoz-Viana, R:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Av Santiago Ramon y Cajal S-N, Alicante 03550, Spain
Barlassina, C:
Univ Milan, Dept Hlth Sci, Genom & Bioinformat Unit, Milan, Italy
Finelli, P:
IRCCS, Ist Auxol Italian, Cytogenet & Mol Genet Lab, Milan, Italy
Univ Milan, Dept Med Biotechnol & Translat Med, Milan, Italy
Gervasini, C:
Univ Milan, Dept Hlth Sci, Med Genet, Milan, Italy
:
Univ Miguel Hernandez, Inst Neurociencias, CSIC, Av Santiago Ramon y Cajal S-N, Alicante 03550, Spain
Russo, S:
IRCCS, Ist Auxol Italian, Cytogenet & Mol Genet Lab, Milan, Italy
Larizza, L:
IRCCS, Ist Auxol Italian, Cytogenet & Mol Genet Lab, Milan, Italy
Green Published, hybrid
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