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Gain and loss of function variants in EZH1 disrupt neurogenesis and cause overlapping neurodevelopmental disorders.

ABSTRACT: Gain and loss of function variants in EZH1 disrupt neurogenesis and cause overlapping neurodevelopmental disorders.

PROVIDER: PRJNA942909 | ENA |

REPOSITORIES: ENA

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Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [ChIP-seq]

Project description:Genetic disruption of chromatin regulators is frequently found in neurodevelopmental disorders (NDDs). While chromatin regulators are attractive therapeutic targets, studies to determine their implication in the etiology of NDDs are limited, preventing advances in diagnosis and treatment strategies. Here, we uncover pathogenic variants in the chromatin modifier Enhancer of Zeste Homologue 1 (EZH1) as the cause of overlapping dominant and recessive NDDs in 19 individuals. EZH1 encodes one of the two alternative histone H3 lysine 27 (H3K27) methyltransferases of the Polycomb Repressive Complex 2 (PRC2). Unlike the other PRC2 subunits, which are associated with the pathogenesis of human cancers and developmental disorders with overgrowth, the implication of EZH1 in human development and disease is largely unknown. Using cellular models and biochemical studies, we demonstrate that EZH1 variants identified in our study alter EZH1 molecularly. While recessive variants are EZH1 loss of function (LOF) variants that impair EZH1 expression, dominant variants are all missense mutations that affect evolutionarily conserved aminoacids likely impacting EZH1 structure or function. Accordingly, we found increased H3K27 methyltransferase activity for two EZH1 missense variants we tested, thus generating EZH1 gain of function (GOF) variants. Furthermore, we show that EZH1 is necessary and sufficient to differentiate neural stem cells in the developing chick embryo neural tube. Finally, using human pluripotent stem cell (hPSC)-derived neural cultures and forebrain organoids, we demonstrate that EZH1 LOF and GOF variation perturbs cortical projection neuron differentiation. Our work identifies EZH1 LOF and GOF variants as the genetic basis of previously undefined recessives and dominant NDDs and uncovers an essential role of EZH1 in regulating neurogenesis.

2023-05-04 | GSE210465 | GEO

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [RNA-seq]

2023-05-04 | GSE227014 | GEO

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause overlapping neurodevelopmental disorders.

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-04 | GSE227016 | GEO

Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [RNA-seq]

Project description:Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [RNA-seq]

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Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [ChIP-seq]

Project description:Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders [ChIP-seq]

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

Project description:Spliceosome malfunction causes neurodevelopmental disorders with overlapping features

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features (fly)

Project description:Spliceosome malfunction causes neurodevelopmental disorders with overlapping features (fly)

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Spliceosome malfunction causes neurodevelopmental disorders with overlapping features (human)

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INTS8 mutations cause severe neurodevelopmental syndrome

Project description:Integrator (INT) is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. INT has at least 14 subunits, but INT germline mutations causing human disease have not been reported. We identified mutations in the Integrator Complex Subunit 8 gene (INTS8) causing a rare neurodevelopmental syndrome. In patient cells we identified significant disturbance of gene expression and RNA processing. Also, we show that injection of ints8 oligonucleotide morpholinos into zebrafish embryos leads to prominent underdevelopment of the head demonstrating the evolutionary conserved requirement of INTS8 in brain development. RNA sequencing was carried out using RNA samples from fibroblasts from two individuals with germline bi-allelic INTS8 mutations and from two healthy individuals

2017-05-17 | E-GEOD-76878 | biostudies-arrayexpress

Polycomb Protein Ezh1 Promotes RNA Polymerase II Elongation

Project description:Polycomb group (PcG) proteins initiate the formation of repressed chromatin domains and regulate developmental gene expression. A mammalian PcG protein, Enhancer of Zeste homolog 2 (Ezh2), triggers transcriptional repression by catalyzing the addition of methyl groups onto lysine-27 of histone H3 (H3K27me2/3)1. This action facilitates the binding of other PcG proteins to histone H3 and compaction of chromatin. Interestingly, there exists a paralog of Ezh2, termed Ezh1, whose primary function remains unclear. Here, we provide evidence for genome-wide association of Ezh1 with active epigenetic marks, RNA polymerase II (PolII) and mRNA production. Ezh1 depletion reduced global PolII occupancy within gene bodies and resulted in delayed transcriptional activation during differentiation of skeletal muscle cells. Conversely, ectopic expression of wild-type Ezh1 led to premature gene activation and rescued PolII-elongation defects in Ezh1-depleted cells. Collectively, these findings reveal an unanticipated role of a PcG protein in promoting mRNA transcription. Examination of 3 different histone modifications, 3 modified forms of RNA polymerase II, Ezh1, Ezh2 and mRNA levels in a skeletal muscle cells at various developmental stages.

2011-11-23 | E-GEOD-25549 | biostudies-arrayexpress

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