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FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer [CAMA1_ChIP-Seq]

ABSTRACT: Using ChIP-Seq analysis of ER+/FGFR1-amplified breast cancer cells and PDXs, we found FGFR1 occupancy at transcription start sites with high overlap with histone modifications associated with active gene transcription. Mass spectrometry analysis of the nuclear and chromatin-bound FGFR1 interactome identified RNA-Polymerase II (Pol II) and FOXA1, with FOXA1 silencing impairing FGFR1 recruitment to chromatin. Transduction of FGFR1(SP-)(NLS) into MCF7 cells resulted in overexpression of nuclear FGFR1 and resistance to antiestrogens. Finally, an expression signature associated with nuclear FGFR1 correlated with endocrine resistance in patients treated with antiestrogens

ORGANISM(S): Homo sapiens

PROVIDER: GSE153285 | GEO | 2021/07/27

REPOSITORIES: GEO

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FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer (RNA-seq)

Project description:Using ChIP-Seq analysis of ER+/FGFR1-amplified breast cancer cells and PDXs, we found FGFR1 occupancy at transcription start sites with high overlap with histone modifications associated with active gene transcription. Mass spectrometry analysis of the nuclear and chromatin-bound FGFR1 interactome identified RNA-Polymerase II (Pol II) and FOXA1, with FOXA1 silencing impairing FGFR1 recruitment to chromatin. Transduction of FGFR1(SP-)(NLS) into MCF7 cells resulted in overexpression of nuclear FGFR1 and resistance to antiestrogens. Finally, an expression signature associated with nuclear FGFR1 correlated with endocrine resistance in patients treated with antiestrogens

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N-glycosylation acts as a switch for FGFR1 trafficking between the plasma membrane and the nuclear envelope

Project description:Fibroblast growth factor receptor 1 (FGFR1) is a heavily N-glycosylated cell surface receptor tyrosine kinase, which in conjunction with fibroblast growth factors (FGFs) transmits signals through the plasma membrane. The balanced FGF/FGFR1 signaling is crucial for the development and homeostasis of human body and aberrant FGFR1 is often observed in various cancers. Besides predominant localization to the plasma membrane, FGFR1 was also detected inside cells, mainly in the nuclear lumen, where it modulates gene expression. However, the exact mechanism of FGFR1 nuclear transport is still unknown. In this study, we generated a glycosylation-free mutant of FGFR1, FGFR1.GF, and demonstrate that it is primarily localized to the nuclear envelope. We show that reintroduction of N-glycans in the D3 domain cannot redirect FGFR1 to the plasma membrane nor exclude the receptor from the nuclear envelope. Reestablishment of N-glycans of the D2 domain largely inhibits FGFR1 accumulation in the nuclear envelope, but receptor still accumulates inside the cell, mainly in the ER. Only the simultaneous presence of N-glycans of the D2 and D3 domains of FGFR1 supports the efficient transport of FGFR1 to the plasma membrane. Intracellular FGFR1.GF displays high level of autoactivation, suggesting the presence of nuclear FGFR1 signaling that is FGF independent. Using mass spectrometry and proximity ligation assay we identified novel binding partners of the nuclear envelope-localized FGFR1, providing insights into its cellular functions. Taken together, our data define N-glycosylation of FGFR1 as a significant regulator of FGFR1 kinase activity, and most importantly a switchable signal for FGFR1 trafficking between the nuclear envelope and the plasma membrane, which, due to the spatial restrictions, shapes the FGFR1 interactome and cellular function.

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FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer

Project description:FGFR1 associates with gene promoters and regulates gene transcription: Implications for endocrine resistance in ER+/FGFR1-amplified breast cancer

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Genome-wide binding profiles of nuclear FGFR1, RXR? and Nur77 in pluripotent mouse Embryonic Stem Cells and during Retinoic Acid-induced differentiation

Project description:We report the genome-wide binding patterns of nuclear FGFR1, RXR? and Nur77 in pluripotenet mESC and as mESC differentiate towared a neuronal lineage in response to high levels of Retinoic Acid treatment in vitro. We also report the genome-wide incorporation of histone varant H3.3 into chromatin specifically during Retinoic Acid-induced differentiation. This study presents nuclear FGFR1 as a global factor that controls genomic function by binding within the promoters of thousands of genes, both alone and in cooperation with RXR, Nur77 and histone H3.3, by targeting consensus DNA sequences of diverse transcription factor families. As such, it identifies a previously unknown, multifaceted form of control of major ontogenic pathways and gene networks targeted by the nuclear form of FGFR1. Examination of nuclear FGFR1, RXR?, and Nur77 binding sites in 2 celluar states. Examination of H3.3 incorporation in 1 cellular state.

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