ZBTB32 performs crosstalk with the glucocorticoid receptor and is crucial in glucocorticoid responses to starvation
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ABSTRACT:
PROVIDER: PRJNA735713 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14749800.fastq.gz | Fastqsanger.gz | |||
| SRR14749789.fastq.gz | Fastqsanger.gz | |||
| SRR14749790.fastq.gz | Fastqsanger.gz | |||
| SRR14749791.fastq.gz | Fastqsanger.gz | |||
| SRR14749792.fastq.gz | Fastqsanger.gz |
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Project description:The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that interacts directly via feedforward and feedback reactions to regulate the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), ZBTB32 (zinc finger and BTB domain containing 32) is a transcription factor with very poorly described functional relevance in physiology. We investigated the importance of ZBTB32 on the HPA axis functioning and found that it is essential for the production of glucocorticoids (GCs) in response to starvation, because ZBTB32-/- mice fail to increase the GC production during prolonged absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32-/- mice, implicating defective cholesterol import as the cause of the poor GC synthesis. Lower GC levels in ZBTB32-/- mice are further associated with aberrations in the metabolic adaptation to starvation, which could potentially explain the progressive weight gain of ZBTB32-/- mice. Moreover, this study identifies that ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production.
2021-06-08 | GSE176277 | GEO
Project description:The hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body's response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32-/- mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32-/- mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32-/- mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production.
| S-EPMC8324811 | biostudies-literature
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses.
2016-06-10 | GSE83191 | GEO
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses. Wild type and Zbtb32-/- resting polyclonal splenic memory B cells were purified by fluorescence activated cell sorting, RNA was extracted, and used for Affymetrix microarray analysis. 5 biological replicates of wild type and Zbtb32-/- cells were included for each cell type.
2016-06-10 | E-GEOD-83191 | biostudies-arrayexpress
Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.
2023-08-23 | GSE200313 | GEO
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses.
2016-06-10 | GSE83193 | GEO
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses.
2016-06-10 | GSE83190 | GEO
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses. CD45.2 wild type and Zbtb32-/- splenocytes from NP-CGG-immune donors were transferred into CD45.1 recipients and challenged with NP-CGG. CD45.2 donor NP-specific plasma cells B cells were isolated from the bone marrow 7 days later. 6 biological replicates of each genotype were performed.
2016-06-10 | E-GEOD-83193 | biostudies-arrayexpress
Project description:Memory B cell responses are more rapid and of greater magnitude than are primary antibody responses. The mechanisms by which these secondary responses are eventually attenuated remain unknown. We demonstrate that the transcription factor ZBTB32 limits the rapidity and duration of antibody recall responses. ZBTB32 is highly expressed by mouse and human memory B cells, but not by their naïve counterparts. Zbtb32-/- mice mount normal primary antibody responses to T-dependent antigens. However, Zbtb32-/- memory B cell-mediated recall responses occur more rapidly and persist longer than do control responses. Microarray analyses demonstrate that Zbtb32-/- secondary bone marrow plasma cells display elevated expression of genes that promote cell cycle progression and mitochondrial function relative to wild-type controls. BrdU labeling and adoptive transfer experiments confirm more rapid production and a cell-intrinsic survival advantage of Zbtb32-/- secondary plasma cells relative to wild-type counterparts. ZBTB32 is therefore a novel negative regulator of antibody recall responses. CD45.2 wild type and Zbtb32-/- splenocytes from NP-CGG-immune donors were transferred into CD45.1 recipients and challenged with NP-CGG. CD45.2 donor NP-specific memory B cells were isolated from the spleen 7 days later. 5-6 biological replicates of each genotype were performed.
2016-06-10 | E-GEOD-83190 | biostudies-arrayexpress
Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.
2023-10-24 | PXD043635 | Pride