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Project description:Pathogenic variants of ubiquitin-specific protease 7 (USP7) cause the neurodevelopmental disorder Hao-Fountain syndrome. However, which of its pleiotropic substrates are relevant for neurodevelopment has remained unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the core USP7 circuitry during neurodifferentiation. USP7 activity is required for the transcriptional programs that direct the differentiation of human ESCs to neural stem cells, and neuronal differentiation of SHSY5Y neuroblastoma cells. In addition to other substrates, including TRIM27, USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligases ncPRC1.1 and ncPRC1.6. We found that BCOR-ncPRC1.1, but not ncPRC1.6 or TRIM27, is a key effector of USP7-dependent neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates the majority of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neuronal differentiation, our results suggest that Hao-Fountain syndrome and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.
2025-03-12 | GSE263491 | GEO
Project description:Pathogenic variants of ubiquitin-specific protease 7 (USP7) cause the neurodevelopmental disorder Hao-Fountain syndrome. However, which of its pleiotropic substrates are relevant for neurodevelopment has remained unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the core USP7 circuitry during neurodifferentiation. USP7 activity is required for the transcriptional programs that direct the differentiation of human ESCs to neural stem cells, and neuronal differentiation of SHSY5Y neuroblastoma cells. In addition to other substrates, including TRIM27, USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligases ncPRC1.1 and ncPRC1.6. We found that BCOR-ncPRC1.1, but not ncPRC1.6 or TRIM27, is a key effector of USP7-dependent neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates the majority of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neuronal differentiation, our results suggest that Hao-Fountain syndrome and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.
2025-03-12 | GSE263490 | GEO
Project description:Pathogenic variants of ubiquitin-specific protease 7 (USP7) cause the neurodevelopmental disorder Hao-Fountain syndrome. However, which of its pleiotropic substrates are relevant for neurodevelopment has remained unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the core USP7 circuitry during neurodifferentiation. USP7 activity is required for the transcriptional programs that direct the differentiation of human ESCs to neural stem cells, and neuronal differentiation of SHSY5Y neuroblastoma cells. In addition to other substrates, including TRIM27, USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligases ncPRC1.1 and ncPRC1.6. We found that BCOR-ncPRC1.1, but not ncPRC1.6 or TRIM27, is a key effector of USP7-dependent neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates the majority of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neuronal differentiation, our results suggest that Hao-Fountain syndrome and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.
2025-03-12 | GSE263489 | GEO
Project description:Hao-Fountain syndrome protein USP7 mediates neuronal differentiation via BCOR-ncPRC1.1
| PRJNA1097638 | ENA
Project description:(RNA-seq-SHSY5Y) Hao-Fountain syndrome protein USP7 mediates neuronal differentiation via BCOR-ncPRC1.1
| PRJNA1097633 | ENA
Project description:(ChIP-seq-SHSY5Y) Hao-Fountain syndrome protein USP7 mediates neuronal differentiation via BCOR-ncPRC1.1
| PRJNA1097640 | ENA
Project description:(RNA-seq-H9) Hao-Fountain syndrome protein USP7 mediates neuronal differentiation via BCOR-ncPRC1.1
| PRJNA1097634 | ENA
Project description:Precise control of protein ubiquitination is essential for brain development, and hence, disruption of ubiquitin signaling networks can lead to neurological disorders. Mutations of the deubiquitinase USP7 cause the Hao-Fountain syndrome (HAFOUS), characterized by developmental delay, intellectual disability, autism, and aggressive behavior. These neurological and behavioral manifestations indicate important unknown roles of USP7 specificially in the nervous system. Here, we report that conditional deletion of USP7 in excitatory neurons in the mouse forebrain triggers diverse phenotypes including growth delay, sensorimotor deficits, learning and memory impairment, and aggressive behavior, resembling clinical features of HAFOUS. USP7 deletion induces neuronal apoptosis in a manner dependent of the tumor suppressor p53. However, most behavioral abnormalities in USP7 conditional mice persist despite p53 loss. Strikingly, USP7 deletion in the brain perturbs the synaptic proteome and dendritic spine morphogenesis independently of p53. Integrated proteomics and subsequent ubiquitin biochemical analysis identify the RNA splicing factor Ppil4 as a novel neuronal substrate of USP7. Consistent with the role of Ppil4 in RNA splicing, loss of USP7 disrupts splicing program of synaptic genes in the cerebral cortex. Improtantly, knockdown of Ppil4 in cortical neurons impairs dendritic spine morphogenesis, phenocopying the effect of USP7 loss on dendritic spines. These findings reveal a novel USP7-Ppil4 ubiquitin signaling link that regulates neuronal connectivity in the developing brain, with implications for our understanding of the pathogenesis of HAFOUS and other neurodevelopmental disorders.
2025-02-25 | GSE280944 | GEO
Project description:BackgroundHao-Fountain syndrome is a neurodevelopmental disorder characterized by global developmental delay, variably impaired intellectual development with significant speech delay and, in some males patients, it has been reported an association with hypogonadism. At present less than 50 cases are reported in literature.Case presentationWe report a case of this rare syndrome in a young female with isolated tubal torsion; our patients had different hospitalizations without treatment but during the last episode we decide to perform an abdominal surgical explortion. This is the first case in Literature with a new USP7 mutation.ConclusionsThis case opens new perspective in this rare syndrome and a review approach to isolated tubal torsion. These symptoms should be always well checked.
| S-EPMC9588229 | biostudies-literature
Project description:ObjectiveThe co-occurrence of pathogenic variants has emerged as a relatively common finding underlying complex phenotypes. Here, we used whole-exome sequencing (WES) to solve an unclassified multisystem clinical presentation.Patients and methodsA 20-year-old woman affected by moderate intellectual disability (ID), dysmorphic features, hypertrichosis, scoliosis, recurrent bronchitis, and pneumonia with bronchiectasis, colelithiasis, chronic severe constipation, and a family history suggestive of autosomal dominant recurrence of polycystic kidney disease was analyzed by WES to identify the genomic events underlying the condition.ResultsFour co-occurring genomic events fully explaining the proband's clinical features were identified. A de novo truncating USP7 variant was disclosed as the cause of Hao-Fountain syndrome, a disorder characterized by syndromic ID and distinctive behavior. Compound heterozygosity for a major cystic fibrosis-causing variant and the modulator allele, IVS8-5T, in CFTR explained the recurrent upper and lower respiratory way infections, bronchiectasis, cholelithiasis, and chronic constipation. Finally, a truncating PKD2 variant co-segregating with polycystic kidney disease in the family allowed presymptomatic disease diagnosis.ConclusionsThe co-occurring variants in USP7 and CFTR variants explained the multisystem disorder of the patient. The comprehensive dissection of the phenotype and early diagnosis of autosomal dominant polycystic kidney disease allowed us to manage the CFTR-related disorder symptoms and monitor renal function and other complications associated with PKD2 haploinsufficiency, addressing proper care and surveillance.
| S-EPMC9141324 | biostudies-literature