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

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

PROVIDER: PRJNA604449 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10999813_1.fastq.gz	Fastqsanger.gz
	SRR10999813_2.fastq.gz	Fastqsanger.gz
	SRR10999814_1.fastq.gz	Fastqsanger.gz
	SRR10999814_2.fastq.gz	Fastqsanger.gz
	SRR10999815.fastq.gz	Fastqsanger.gz

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

Project description: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

2020-09-27 | GSE144648 | GEO

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

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

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

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: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

Differential quantitative proteome analysis of cerebellar flocculus on oculomotor behavior training mouse model

Project description:Oculomotor behavior model system is commonly employed to study the neural circuits and the cellular mechanisms underlying neural integration related to motor behavior. The flocculus is a small lobe at the posterior border of the middle cerebellar and involved in motor control to aid in the oculomotor system in the brain. However, only several studies have investigated the molecular mechanism of learning and memory in flocculus region using another approach than proteomics.

2020-03-20 | PXD008433 | Pride

Cerebellar organoids model cell type-specific FOXP2 expression during human cerebellar development

Project description:Cerebellar organoids differentiated from human induced pluripotent stem cells (iPSCs) contain key cerebellar cell types and are increasingly used to study cerebellar diseases. In this study, we demonstrate the potential of cerebellar organoids for studying features of early human cerebellar development. Forkhead box protein P2 (FOXP2) is a transcription factor associated with speech and language development that is highly expressed in the developing brain. However, little attention has been directed to the study of FOXP2 in the early developing cerebellum. Here we used CRISPR gene editing in human iPSCs to generate a fluorescent FOXP2-reporter line. By combining transcriptomic analysis of iPSC-derived cerebellar organoids with published cerebellar datasets, we describe the expression and identify potential downstream targets of FOXP2 in the early developing human cerebellum. Our results highlight expression of FOXP2 in early human Purkinje cells and cerebellar nuclei neurons, and the vulnerability of these cell populations to neurodevelopmental disorders. Our study demonstrates the power of cerebellar organoids to model early human developmental processes and disorders.

2024-12-19 | GSE285003 | GEO

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