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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

ABSTRACT: As part of characterizing the novel pogz deficiency mouse model, we performed RNA-Seq from cerebellum and hippocampus of adult mice to discover Pogz targets and changes in gene expression that might explain the phenotypes we see in those mice

ORGANISM(S): Mus musculus

PROVIDER: GSE144648 | GEO | 2020/09/27

REPOSITORIES: GEO

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Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Project description:Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

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Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice.

Project description:Several genes implicated in autism spectrum disorder (ASD) are chromatin regulators, including POGZ. The cellular and molecular mechanisms leading to ASD impaired social and cognitive behavior are unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior as well as unveiling the underlying mechanisms. Here, we generate a brain specific conditional knockout mouse model deficient for Pogz, an ASD risk gene. We demonstrate that Pogz deficient mice show microcephaly, growth impairment, increased sociability, learning and motor deficits, mimicking several of the human symptoms. At the molecular level, luciferase reporter assay indicates that POGZ is a negative regulator of transcription. In accordance, in Pogz deficient mice we find a significant upregulation of gene expression, most notably in the cerebellum. Gene set enrichment analysis revealed that the transcriptional changes encompass genes and pathways disrupted in ASD, including neurogenesis and synaptic processes, underlying the observed behavioral phenotype in mice. Physiologically, Pogz deficiency is associated with a reduction in the firing frequency of simple and complex spikes and an increase in amplitude of the inhibitory synaptic input in cerebellar Purkinje cells. Our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and behavioral abnormalities in ASD.

| S-EPMC7673123 | biostudies-literature

Author Correction: Pogz deficiency leads to transcription dysregulation and impaired cerebellar activity underlying autism-like behavior in mice.

Project description: Not available

| S-EPMC8211799 | biostudies-literature

Gene expression data from E14.5 Pogz-WT and Pogz-KO fetal livers.

Project description:Fetal and adult β-globin gene expression is tightly regulated during human development. Fetal globin genes are transcriptionally silenced during embryogenesis through the process of hemoglobin switching. Efforts to understand the transcriptional mechanism(s) behind fetal globin silencing have led to novel strategies to derepress fetal globin expression in the adult, which could alleviate symptoms in hereditary b-globin disorders including sickle cell disease (SCD) and β-thalassemia. We identified a novel zinc finger protein, pogo transposable element with zinc finger domain (Pogz), expressed in mouse and human hematopoietic stem and progenitor cells, which represses embryonic b-like globin gene expression in mice. Ablation of Pogz expression in adult hematopoietic cells in vivo results in persistence of embryonic b-like globin expression without significantly affecting erythroid development or mouse survival. Elevated embryonic β-like globin expression correlates with reduced expression of Bcl11a, a known repressor of embryonic β-like globin expression, in Pogz-/- fetal liver cells. Pogz binds to the Bcl11a promoter, and, to erythroid specific intragenic regulatory regions. Importantly, Pogz+/- mice develop normally, but show elevated embryonic b-like globin expression in peripheral blood cells, demonstrating that reducing Pogz levels results in persistence of embryonic b-like globin expression. Finally, knockdown of POGZ in primary human CD34+ hematopoietic stem and progenitor cell derived erythroblasts, reduces BCL11A expression and increases fetal hemoglobin expression. These findings are significant since new therapeutic targets and strategies are needed to treat the increasing global burden of b-globin disorders.

2018-06-21 | GSE113503 | GEO

POGZ loss increases TGFβ signaling and potentiates TNBC metastasis

Project description:The pogo transposable element derived zinc finger protein, POGZ, is notably associated with autism-like or intellectual disabilities through its role in gene transcription. Indeed, many proteins involved in neurological development are often dysregulated in cancer. We provide the first experimental evidence that POGZ influences the growth and metastatic spread of triple negative breast cancers (TNBC). Utilizing a well-characterized immunocompetent model of TNBC, we show that POGZ exerts a dual role, both as a tumor promoter and metastasis suppressor. Mechanistically, we show that POGZ loss potentiates TGFβ pathway activation in TNBC, to exert cytostatic effects while simultaneously increasing the mesenchymal and migratory properties of breast tumors. Finally, we demonstrate that whereas POGZ levels are elevated in human breast cancers, the most aggressive TNBC tumors, including those with increased mesenchymal and metastatic properties, dampen POGZ levels, associated with inferior clinical outcomes. Combined these data suggest that POGZ is a critical regulator of the early stages of metastatic cascade

2024-07-31 | GSE247628 | GEO

Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

Project description:Deleterious genetic variants in POGZ, which encodes the chromatin regulator Pogo Transposable Element with ZNF Domain protein, are strongly associated with autism spectrum disorder (ASD). Although it is a high confidence ASD risk gene, the neurodevelopmental functions of POGZ remain unclear. Here we reveal the genomic binding of POGZ in the developing forebrain at euchromatic loci and gene regulatory elements (REs). We profile chromatin accessibility and gene expression in Pogz-/- mice and show that POGZ promotes the active chromatin state and transcription of clustered synaptic genes. We further demonstrate that POGZ forms a nuclear complex and co-occupies loci with ADNP, another high-confidence ASD risk gene, and provide evidence that POGZ regulates other neurodevelopmental disorder risk genes as well. Our results reveal a neurodevelopmental function of an ASD risk gene and identify molecular targets that may elucidate its function in ASD.

2021-11-05 | GSE187010 | GEO

Gene expression data from E14.5 Pogz-WT and Pogz-KO fetal livers.

Project description:Gene expression data from E14.5 Pogz-WT and Pogz-KO fetal livers.

| PRJNA451370 | ENA

A Convergent Mechanism of High Risk Factors ADNP and POGZ in Neurodevelopmental Disorders

Project description:We performed RNAseq experiments to examine genome-wide transcriptional changes in PFC of shRNA-Adnp and shRNA-Pogz KD mice compared to GFP injected controls mice.

2021-11-17 | GSE188865 | GEO

Ectopic cerebellar cell migration causes maldevelopment of Purkinje cells and abnormal motor behaviour in Cxcr4 null mice

Project description:Transcriptome analysis revealed the most significantly affected pathways in the Cxcr4 deficient developing cerebellum are involved in extra cellular matrix receptor interactions and focal adhesion We isolated the cerebellum WT (n=8) and CXCR4 KO(n=7) P1 mice, and run illumina mice gene expression array to compare the gene expression pattern between this two groups.

2013-07-12 | E-GEOD-48788 | biostudies-arrayexpress

Galnt17 loss-of-function leads to developmental delay, abnormal coordination, activity, and social interactions, with cerebellar vermis pathology

Project description:GALNT17 encodes a N-acetylgalactosaminyltransferase (GalNAc-T) protein specifically involved in mucin-type O-linked glycosylation of target proteins, a process important for cell adhesion, cell signaling, neurotransmitter activity, neurite outgrowth, and neurite sensing. GALNT17, also known as WBSCR17, is located at the edge of the Williams-Beuren Syndrome (WBS) critical region and adjacent to the AUTS2 locus, genomic regions associated with neurodevelopmental phenotypes that are thought to be co-regulated. Although previous data have implicated Galnt17 in neurodevelopment, the in vivo functions of this gene have not been investigated. In this study, we have analyzed behavioral, brain pathology, and molecular phenotypes exhibited by Galnt17 knockout (Galnt17-/-) mice. We show that Galnt17-/- mutants exhibit developmental neuropathology within the cerebellar vermis, along with abnormal activity, coordination, and social interaction deficits. Transcriptomic and protein analysis revealed reductions in both mucin type O-glycosylation and heparan sulfate synthesis in the developing mutant cerebellum along with disruption of pathways central to neuron differentiation, axon pathfinding, and synaptic signaling, consistent with the mutant neuropathology. These brain and behavioral phenotypes and molecular data confirm a specific role for Galnt17 in brain development and suggest new clues to factors that could contribute to phenotypes in certain WBS and AUTS2 syndrome patients.

2023-05-03 | GSE180040 | GEO

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