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Transcriptome analysis of fetal kidney RNA from GR-null and control mice at E18.5

ABSTRACT: Glucocorticoid steroid hormones play essential roles for maturation and growth of many fetal organs including the lung and heart, yet the kidney-specific roles are not well characterised. Glucocorticoids activate the intracellular glucocorticoid receptor (GR) that acts primarily as nuclear transcriptional regulators. We analysed the effect of loss of GR expression on the fetal kidney transcriptome at E18.5 by RNA sequencing. Total RNA was extracted from control (n=4) and GR-null (n=3) kidneys. Loss of GR expression resulted in 2473 differentially expressed genes (FDR < 0.05), 288 genes with absolute LogFC > 1 & FDR < 0.05, which identified 16 upregulated and 25 downregulated primary ciliary genes (FDR < 0.05). Primary cilia are cell signalling and environment sensing organelles that protrude from cell membranes and play important roles during embryogenesis and tissue homeostasis. Little is known of the cellular pathways regulating ciliogenesis. Our findings indicate a role of glucocorticoid signalling in primary cilia formation in renal tubular cells of the developing mouse kidney.

ORGANISM(S): Mus musculus

PROVIDER: GSE290962 | GEO | 2025/04/15

REPOSITORIES: GEO

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Project description:The glucocorticoid receptor (GR) regulates gene expression throughout the human genome in a cell-type-specific manner, governing various aspects of homeostasis. The influence of this transcriptional regulator is seen in multiple pathologies, including cancer. Pharmacological activation of the GR is frequently used to alleviate side-effects caused by therapy for patients with various non-lymphoid solid (i.e. non-hematologic) cancers; however, prior studies have shown that this treatment might also have anti-proliferative action on cancer cells. Nonetheless, the molecular underpinnings of glucocorticoid action and its direct effectors in non-lymphoid solid cancers remain elusive. Here, we study the molecular mechanisms of glucocorticoid response in non-lymphoid solid cancers models, focusing on lung cancer. Activation of the GR induces reversible cancer cell dormancy in which cells are tolerant to large array of anti-cancer drugs. This state transition is accompanied by induction of growth factor survival signalling (IGF-1R) and acquired vulnerability to inhibitors of this pathway, both in vitro and in vivo. The observed phenotype is dependent on a single GR target gene - CDKN1C, which encodes for a cell cycle inhibitor protein p57. We have discovered an upstream distal enhancer of CDKN1C, which through GR-induced chromatin looping regulates the expression of this key gene, as confirmed in human tumour specimens. Furthermore, we demonstrate that the SWI/SNF complex composition fine-tunes the GR transcriptional activity at the CDKN1C locus, allowing for precise regulation of cell dormancy induction. Collectively, we show that SWI/SNF-facilitated regulation of CDKN1C underlines GR-induced reversible drug-tolerant state in cancer cells. These insights illustrate the importance of GR signalling in non-lymphoid solid cancer biology, particularly in lung cancer, and warrant caution for use of glucocorticoids in treatment of anti-cancer therapy related side-effects.

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Transcriptome analysis of fetal kidney RNA from GR-null and control mice at E18.5

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