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Hypoxia Inducible Factor 1α-driven steroidogenesis impacts systemic hematopoiesis

ABSTRACT: Glucocorticoids regulate hematopoiesis, but how chronic elevation of endogenous glucocorticoid production affects hematopoietic stem cell (HSC) function and immune cell development remains incompletely understood. Using an adrenocortical cell-specific HIF1α (Hypoxia inducible Factor-1α)-deficient mouse model (P2H1Ad.Cortex) resulting in elevated glucocorticoid (GC) levels, we here demonstrate that sustained GC exposure promotes hematopoietic stem and progenitor cell (HSPC) expansion while shifting HSCs toward a more quiescent and metabolically restrained state. Functionally, these HSCs exhibited enhanced regenerative potential, as evidenced by superior donor chimerism in transplantation assays. In addition, we observed a striking increase in myeloid progenitors, as well as in their progeny (monocytes and granulocytes). Conversely, B-cell differentiation in the bone marrow was severely impaired, with a strong block at the pre-pro-B cell stage. To determine whether these phenotypes were driven by glucocorticoid receptor (GR) signaling, we performed transplantation experiments using GR-deficient or WT control bone marrow into P2H1Ad.Cortex or WT littermate recipients. This approach decisively demonstrated that both the increase in myeloid cells and the block in B-cell differentiation were GR-dependent, confirming that GC-GR signaling plays a pivotal role in shaping hematopoiesis. Taken together, our findings clearly suggest a direct role for chronic glucocorticoid exposure in regulating HSC function, lineage differentiation, and stress hematopoiesis. The mouse model of adrenocortical cell-specific HIF1α deficiency provides a valuable tool to study the long-term effects of elevated glucocorticoid levels on hematopoietic regulation and may provide further insight into hematologic disorders associated with chronic therapeutic glucocorticoid administration.

ORGANISM(S): Mus musculus

PROVIDER: GSE292877 | GEO | 2025/09/03

REPOSITORIES: GEO

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Project description:Posttranscriptional regulation is emerging as a key factor in glucocorticoid (GC)-mediated gene regulation. We investigated the role of the human glucocorticoid receptor (GR) as an RNA-binding protein and its effect on mRNA turnover in human airway epithelial cells. Cell treatment with the potent GC budesonide accelerated the decay of CCL2 mRNA (t1/2=8±1 min vs. 62±17 min in DMSO-treated cells) and CCL7 mRNA (t1/2=15±4 min vs. 114±37 min), but not that of CCL5 mRNA (t1/2=231±8 min vs. 266±5 min) in the BEAS-2B cell line. This effect was inhibited by pre-incubation with an anti-GR antibody, indicating that GR itself plays a role in the turnover of these transcripts. Co-immunoprecipitation and biotin pulldown experiments showed that GR associates with CCL2 and CCL7 mRNAs, but not CCL5 mRNA. These methods confirmed CCL2 mRNA targeting by GR in human primary airway epithelial cells. Association of the GR was localized to the 5’UTR of CCL2 mRNA, and further mapped to nucleotides 44-60. The collection of transcripts associated with GR, identified by immunoprecipitation of GR-mRNA complexes followed by microarray analysis, revealed 479 transcripts that associated with GR. Computational analysis of the primary sequence and secondary structures of these transcripts yielded a GC-rich motif, which was shown to bind to GR in vitro. This motif was used to predict binding of GR to an additional 7889 transcripts. These results indicate that cytoplasmic GR interacts with a subset of mRNA through specific sequences and can regulate turnover rates, suggesting a novel posttranscriptional role for GR as an RNA-binding protein. The BEAS-2B cell line is derived from human tracheal epithelium transformed by an adenovirus 12-SV40 hybrid virus. For isolation of glucocorticoid receptor-associated transcripts, cytoplasmic lysates obtained from 1.6x107 cells/condition, 4 replicates per condition, were used to generate a collection of transcripts associated with GR by immunoprecipitation of the GR-mRNA complexes. The RNA from these IP's were extracted and labeled with the Illumina TotalPrep RNA Amplification Kit which generates biotin-labeled cRNA. This was hybridized to Illumina's Sentrix HumanRef-8,v3 Expression BeadChips. The data from 3 replicates of GR-IP and 4 replicates of Control-IP were used for global analysis of GR-mRNA interactions.

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Hypoxia Inducible Factor 1α-driven steroidogenesis impacts systemic hematopoiesis

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