UBR5 Forms Ligand-Dependent Complexes on Chromatin to Regulate Nuclear Hormone Receptor Binding [RNA-Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE213793 | GEO | 2023/07/20
REPOSITORIES: GEO
Similar Datasets
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are important therapeutic targets in malignancy. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant: the oncogenic PML-RARA fusion between PML and the retinoic acid receptor (RARA) drives acute promyelocytic leukemia and degradation of PML-RARA induced by all-trans-retinoic acid (ATRA) is required for anti-tumor activity. We identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | GSE213742 | GEO
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD041749 | Pride
Project description:Nuclear hormone receptors (NRs) are ligand-binding transcription factors that are widely targeted therapeutically. Hormone binding triggers NR activation and their subsequent proteasomal degradation through unknown ligand-dependent ubiquitin ligase machinery. NR degradation is therapeutically relevant. Efficacy of all-trans-retinoic acid (ATRA) for the treatment of acute promyelocytic leukemia requires degradation of the oncogenic fusion between the Promyelocytic Leukemia Protein (PML) with the Retinoic Acid Receptor Alpha (RARA). Here we use CRISPR-based screens to identify the HECT E3 ubiquitin ligase UBR5 as a ligase for PML-RARA and RARA and observe an agonist-dependent association between RARA and UBR5, which occurs directly on chromatin to regulate transcription. We present the cryo-EM structure of full-length human UBR5 and identify a Leu-X-X-Leu-Leu (LxxLL) binding motif that associates with a conserved degron in RARA. A high-resolution crystal structure of the RARA ligand binding domain in complex with this LxxLL motif shows how UBR5 binding is mutually exclusive with nuclear co-activator engagement. We demonstrate that UBR5 utilizes this conserved degron to additionally regulate hormone dependent protein stability for the glucocorticoid, progesterone, and vitamin D receptors. Our work establishes UBR5-driven NR degradation as an integral regulator of transcriptional signaling by nuclear hormones.
2023-07-20 | PXD040953 | Pride
Project description:To identify the top 20 up-regulated genes in NB4 TRIB3 shRNA cells in comparison with NB4 control shRNA cells, we examined the microarray gene expression profile of these groups above. Despite the fact that combined therapy of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapy dramatically improves the prognosis of patients with acute promyelocytic leukemia (APL), these regimens can cause systemic infections and secondary leukemias. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing its sumoylation, ubiquitylation and degradation. This represses PML nuclear body assembly, p53-mediated senescence, cell differentiation, and supports cellular self-renewal. Genetically inhibiting Trib3 expression or disturbing the TRIB3/PML-RARa interaction produces potent therapeutic efficacy against APL and has synergic anti-APL effects when used in combination with ATRA or ATO by promoting PML-RARa degradation and PML expression. Our study provides new insight into APL pathogenesis and a new therapeutic option against APL.
2017-05-12 | GSE95637 | GEO
Project description:To identify the top 20 up-regulated genes in CD34+ cells from AML patients in comparison with healthy donors, we examined the microarray gene expression profile of CD34+ blasts from patients with newly diagnosed AML vs CD34+ normal cells from healthy donors. Despite the fact that combined therapy of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapy dramatically improves the prognosis of patients with APL, these regimens can cause systemic infections and secondary leukemias. Here we report that expression of the pseudokinase Tribble 3 (TRIB3) associates positively with APL progression and therapeutic resistance. The elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing its sumoylation, ubiquitylation and degradation. This represses PML nuclear body assembly, p53-mediated senescence, cell differentiation, and supports cellular self-renewal. Genetically inhibiting Trib3 expression or disturbing the TRIB3/PML-RARa interaction produces potent therapeutic efficacy against APL and has synergic anti-APL effects when used in combination with ATRA or ATO by promoting PML-RARa degradation and PML expression. Our study provides new insight into APL pathogenesis and a new therapeutic option against APL.
2017-05-12 | GSE90062 | GEO
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE209833 | GEO
Project description:Acute Promyelocytic Leukemia (APL) is a fatal subtype of leukemia driven by the translocation between genes encoding the Promyelocytic Leukemia (PML) protein and the Retinoic Acid Receptor alpha (RARa) protein. We use mouse hematopoietic progenitor cells expressing PML-RARa and dissect the dynamic changes in the epigenome, transcriptome and genome architecture triggered by the expression of this oncogenic transcription factor during leukemic transformation. We find that PML-RARa induces a continuum of topologic and transcriptional alterations, mostly affecting distal regulatory elements. Furthermore, we identify Klf4 ― a master regulator of hematopoietic differentiation ― as an early mis-regulated gene during leukemogenesis, and deconstruct the dynamic alterations in long-range interactions, histone modifications and transcriptional output triggered by PML-RARa expression at the Klf4 locus. Our study provides a comprehensive overview of the dynamic genomic and transcriptomic alterations induced by PML-RARa, which ultimately block hematopoietic differentiation and induce leukemic transformation.
2022-06-09 | GSE151837 | GEO
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We apply a novel computational deep learning strategy to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE215101 | GEO
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE173754 | GEO
Project description:The PML-RARA fusion protein is the hallmark driver of Acute Promyelocytic Leukemia (APL) and disrupts retinoic acid signaling, leading to wide-scale gene expression changes and uncontrolled proliferation of myeloid precursor cells. While known to be recruited to binding sites across the genome, its impact on gene regulation and expression is under-explored. Using integrated multi-omics datasets, we characterize the influence of PML-RARA binding on gene expression and regulation in an inducible cell line model and APL patient ex vivo samples. We find that genes whose regulatory elements recruit PML-RARA are not uniformly transcriptionally repressed, as commonly suggested, but also may be upregulated or remain unchanged. We develop a novel, computational machine learning application to deconvolute the complex, local transcription factor binding site environment at PML-RARA bound positions to reveal distinct signatures that modulate how PML-RARA directs the transcriptional response.
2022-12-14 | GSE173753 | GEO