Ontology highlight
ABSTRACT:
PROVIDER: PRJNA485028 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7657940_1.fastq.gz | Fastqsanger.gz | |||
| SRR7657940_2.fastq.gz | Fastqsanger.gz | |||
| SRR7657941_1.fastq.gz | Fastqsanger.gz | |||
| SRR7657941_2.fastq.gz | Fastqsanger.gz | |||
| SRR7657942_1.fastq.gz | Fastqsanger.gz |
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Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
2024-12-09 | GSE283524 | GEO
Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
2024-12-09 | GSE283525 | GEO
Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
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Project description:Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease associated with microcephaly and poor neurodevelopmental outcomes. Here we show that the Ohia HLHS mouse model, with mutations in Sap130, a chromatin modifier, and Pcdha9, a cell adhesion protein, also exhibits microcephaly associated with mitotic block and increased apoptosis leading to impaired cortical neurogenesis. Transcriptome profiling, DNA methylation, and Sap130 ChIPseq analyses all demonstrated dysregulation of genes associated with neurogenesis, cognitive impairment and autism. This involved perturbation of REST transcriptional regulation of neurogenesis, disruption of CREB signaling regulating synaptic plasticity, and defects in neurovascular coupling mediating cerebral blood flow. Adult mice harboring either the Pcdha9 mutation, which showed normal brain anatomy, or forebrain-specific Sap130 deletion via Emx1-Cre, which showed microcephaly, both demonstrated learning and memory deficits and autism-like behavior. These novel findings provide mechanistic insights indicating the adverse neurodevelopment in HLHS may involve cell autonomous/nonautonomous defects and epigenetic dysregulation.
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Project description:Overgrowth with Intellectual Disability (OGID) is characterized by generalized overgrowth, including a head circumference and/or height ≥ 2 standard deviations (s.d.) above the mean, accompanied by mild to moderate intellectual disability. Sotos Syndrome, the most common form of OGID, results from loss-of-function (LoF) mutations in NSD1, which encodes a histone methyltransferase. Another major OGID subtype, Tatton-Brown-Rahman syndrome, is caused by LoF mutations in DNMT3A, encoding a de novo DNA methyltransferase. In contrast, gain-of-function (GoF) mutations in DNMT3A cause Heyn-Sproul-Jackson syndrome, characterized by growth restriction and microcephaly. We hypothesize that NSD1 LoF and DNMT3A LoF mutations share a convergent DNA methylation signature that is distinct from the pattern seen in DNMT3A GoF mutations. To test this, we generated human embryonic stem cell lines carrying these growth syndrome-associated mutations in NSD1 and DNMT3A, profiled their DNA methylation patterns using the Illumina EPIC array, and analyzed both shared and unique methylation phenotypes.
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Project description:Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. Studies during brain development reveal disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and highlight precocious neuronal differentiation as the mechanism for microcephaly. In contrast, adult studies reveal that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral features including hyperactivity, hypotonia, and social alterations, with more severe phenotypes in males. Overall, these studies provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.
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Project description:Human genetics have defined a new autism-associated syndrome caused by loss-of-function mutations in MYT1L, a transcription factor known for enabling fibroblast-to-neuron conversions. However, how MYT1L mutation causes autism, ADHD, intellectual disability, obesity, and brain anomalies is unknown. Here, we develop a mouse model of this syndrome. Physically, Myt1l haploinsufficiency causes obesity, white-matter thinning, and microcephaly in the mice, mimicking clinical phenotypes. Studies during brain development reveal disrupted gene expression, mediated in part by loss of Myt1l gene target activation, and highlight precocious neuronal differentiation as the mechanism for microcephaly. In contrast, adult studies reveal that mutation results in failure of transcriptional and chromatin maturation, echoed in disruptions in baseline physiological properties of neurons. This results in behavioral features including hyperactivity, hypotonia, and social alterations, with more severe phenotypes in males. Overall, these studies provide insight into the mechanistic underpinnings of this disorder and enable future preclinical studies.
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