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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [RNA-seq]

ABSTRACT: 7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [RNA-seq]

PROVIDER: PRJNA1088436 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28353239_1.fastq.gz	Fastqsanger.gz
	SRR28353239_2.fastq.gz	Fastqsanger.gz
	SRR28353240_1.fastq.gz	Fastqsanger.gz
	SRR28353240_2.fastq.gz	Fastqsanger.gz
	SRR28353241_1.fastq.gz	Fastqsanger.gz

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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability

Project description:7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability

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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [RNA-seq]

Project description:Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup). Both neurodevelopmental disorders (NDDs) feature mild to moderate intellectual disability, accompanied by symmetrically opposite neurocognitive and behavioral features. Although significant progress has been made in understanding the molecular mechanisms underlying 7q11.23-related pathophysiologies, the interplay between different layers of gene expression and the propagation of opposite symmetry arising from CNV remains elusive. Here, we uncovered 7q11.23 dosage-dependent symmetrically opposite dynamics in neuronal differentiation and intrinsic excitability. By integrating transcriptomics, translatomics and proteomics of patient-derived and isogenic induced neurons, we found that genes related to neuronal transmission follow 7q11.23 dosage and are transcriptionally controlled, while translational factors and ribosomal genes are post-transcriptionally buffered. Consistently, we found a deregulated mTOR pathway, with phospho-S6 (pS6) being downregulated in WBS and upregulated in 7Dup. Surprisingly phospho-4E-BP (p4E-BP) was going in the opposite direction, reflecting the total 4E-BP levels, thus highlighting the different roles of pS6 and p4E-BP during neurogenesis. Therefore, our work emphasizes the importance of multilayer research when investigating complex NDDs, highlighting ribosomal biogenesis and paving the way for novel treatments by uncoupling the role of pS6 and p4E-BPs in NDDs.

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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [ribosome footprinting]

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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [ribosome footprinting]

Project description:7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability [ribosome footprinting]

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7q11.23 CNV altered proteome in iPSC differentiating neurons

Project description:Copy number variations (CNVs) at 7q11.23 cause Williams-Beuren (WBS) and 7q microduplication syndromes (7Dup), two neurodevelopmental disorders with shared and opposite cognitive-behavioral phenotypes. Using patient-derived and isogenic neurons, we integrated transcriptomics, translatomics and proteomics to elucidate the molecular underpinnings of this dosage effect. We found that 7q11.23 CNVs cause opposite alterations in neuronal differentiation and neuronal excitability. Here, the 7q11.23 CNV altered proteome in iPSC differentiating neurons was measured by a fast SWATH-MS method.

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7q11.23 CNV alters ribosomal biogenesis, mTOR and neuronal intrinsic excitability

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7q11.23 dosage-dependent dysregulation in the human pluripotent state primes aberrant transcriptional programs in disease-relevant lineages (RNAseq)

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.

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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 (7dup). 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.

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