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Changes in nascent transcripts upon glucocorticoid stimulation in macrophages

ABSTRACT: Glucocorticoids are widely prescribed anti-inflammatory drugs with tissue-specific effects. Beneficial anti-inflammatory effects are caused in cells of the immune system whereas metabolic adverse effects of glucocorticoid therapy are seen in metabolic tissues such as liver. The glucocorticoid receptor (GR), a nuclear receptor targeted by glucocorticoids, bind its DNA response elements upon ligand exposure in a tissue-specific manner. Tissue-specific GR binding patterns depend on the access of its binding sites, which determines the tissue-specific glucocorticoid response. Here, we investigated this response by nascent RNAseq in murine bone marrow-derived macrophages (BMDMs) after stimulation with lipopolysaccharide (LPS) and dexamethasone (Dex). After labelling newly synthesized transcripts with 4-thiouracile (4sU), we identified macrophage-specific non-coding transcripts expressed at intergenic GR binding sites. Those transcripts are regulated by the GR and correlate with its anti-inflammatory function in macrophages. Those findings add another layer to the mechanisms underpinning GR's tissue-specific gene regulation and represent potential drug targets in anti-inflammatory therapy and/or management of adverse effects in glucocorticoid therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE186629 | GEO | 2021/12/31

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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Changes in nascent transcripts upon glucocorticoid stimulation in macrophages

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