Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA777259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR16704800.fastq.gz | Fastqsanger.gz | |||
| SRR16704801.fastq.gz | Fastqsanger.gz | |||
| SRR16704802.fastq.gz | Fastqsanger.gz | |||
| SRR16704803.fastq.gz | Fastqsanger.gz | |||
| SRR16704804.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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
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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.
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