POGZ loss increases TGFβ signaling and potentiates TNBC metastasis
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ABSTRACT:
PROVIDER: PRJNA1039840 | ENA |
REPOSITORIES: ENA
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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: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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