Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene

Kan, Mengyuan; Diwadkar, Avantika R.; Shuai, Haoyue; Joo, Jaehyun; Wang, Alberta L.; Ong, Mei-Sing; Sordillo, Joanne E.; Iribarren, Carlos; Lü, Meng; Hernandez‐Pacheco, Natalia; Pérez-García, Javier; Gorenjak, Mario; Potočnik, Uroš; Burchard, Esteban G.; Pino-Yanes, María; Wu, Ann Chen; Himes, Blanca E.

doi:10.1016/j.jaci.2021.11.025

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…Mechanistically, BIRC3 expression was independently induced by glucocorticoids acting via the GR. Indeed, multiple GR bindings sites have been identified at the BIRC3 locus in response to glucocorticoids [ 35 , 72 , 73 ]. Thus, it is plausible that the presence of GR binding to conventional glucocorticoid response elements (GREs) could offset repression that occurs via other mechanisms [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, such interactions are proposed for a ~1 kb BIRC3 promoter region upstream of transcription start that contains putative NF-κB and GRE sites [ 76 ]. However, it is salient to note that this previously reported region does not contain the main GR binding site identified by ChIP-seq [ 35 , 72 , 73 ], and it is therefore likely that important facets of this interaction remain to be described. Indeed, while the current analyses support roles for NF-κB and GR in the rapid induction of BIRC3 by IL1B, TNF and glucocorticoids, how these pathways then interact to produce synergistic increases in BIRC3 expression was not specifically addressed.…”

Section: Discussionmentioning

confidence: 99%

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Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells

et al. 2023

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Roles for the baculoviral inhibitor of apoptosis repeat-containing (BIRC) genes, BIRC2 and BIRC3, may include signaling to the inflammatory transcription factor, nuclear factor-κB (NF-κB) and protection from cell death. However, distinct functions for each BIRC are not well-delineated. Given roles for the epithelium in barrier function and host defence, BIRC2 and BIRC3 expression was characterized in pulmonary epithelial cell lines and primary human bronchial epithelial cells (pHBECs) grown as undifferentiated cells in submersion culture (SC) or as highly differentiated cells at air-liquid interface (ALI). In A549 cells, interleukin-1β (IL1B) and tumor necrosis factor α (TNF) induced BIRC3 mRNA (~20-50-fold), with maximal protein expression from 6–24 h. Similar effects occurred in BEAS-2B and Calu-3 cells, as well as SC and ALI pHBECs. BIRC2 protein was readily detected in unstimulated cells, but was not markedly modulated by IL1B or TNF. Glucocorticoids (dexamethasone, budesonide) modestly increased BIRC3 mRNA and protein, but showed little effect on BIRC2 expression. In A549 cells, BIRC3 mRNA induced by IL1B was unchanged by glucocorticoids and showed supra-additivity with TNF-plus-glucocorticoid. Supra-additivity was also evident for IL1B-plus-budesonide induced-BIRC3 in SC and ALI pHBECs. Using A549 cells, IL1B- and TNF-induced BIRC3 expression, and to a lesser extent, BIRC2, was prevented by NF-κB inhibition. Glucocorticoid-induced BIRC3 expression was prevented by silencing and antagonism of the glucocorticoid receptor. Whereas TNF, but not IL1B, induced degradation of basal BIRC2 and BIRC3 protein, IL1B- and TNF-induced BIRC3 protein remained stable. Differential regulation by cytokines and glucocorticoids shows BIRC2 protein expression to be consistent with roles in rapid signaling events, whereas cytokine-induced BIRC3 may be more important in later effects. While TNF-induced degradation of both BIRCs may restrict their activity, cytokine-enhanced BIRC3 expression could prime for its function. Finally, shielding from glucocorticoid repression, or further enhancement by glucocorticoid, may indicate a key protective role for BIRC3.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells

et al. 2023

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“…In the reviewed period, four candidate gene studies have explored susceptibility variants for response to inhaled corticosteroids (ICS) [60,61,63,70], long-acting beta2agonists [55], or montelukast [58] using AEs as a clinical endpoint. Four of them assessed asthma-related genes: IL1RL1 [60] and CRHR1 [61] for ICS, ADRB2 [55] for LABA, and LTA4H [58] for montelukast response.…”

Section: Candidate-gene Association Studies Most Candidate-gene Assoc...mentioning

confidence: 99%

“…Four of them assessed asthma-related genes: IL1RL1 [60] and CRHR1 [61] for ICS, ADRB2 [55] for LABA, and LTA4H [58] for montelukast response. The other two combined or integrated multiple omics to prioritize candidate genes [63,70] with AEs -despite ICS use-in Hispanics/Latinos, African Americans, and Europeans [63].…”

Section: Candidate-gene Association Studies Most Candidate-gene Assoc...mentioning

confidence: 99%

Asthma Exacerbations: The Genes Behind the Scenes

Luis¹,

Forno²,

Celedón³

et al. 2023

J Investig Allergol Clin

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The clinical and socioeconomic burden of asthma exacerbations (AEs) represents a major public health problem. In the last four years, there has been an increase in ethnic diversity in candidate-gene and genome-wide association studies (GWAS) of AEs, which in the latter case has led to the identification of novel genes and underlying pathobiological processes. Pharmacogenomics, admixture mapping analyses, and the combination of multiple “omic” layers have contributed to prioritizing genomic regions of interest and/or understanding the functional consequences of genetic variation. Despite this, the field still lags behind the genomics of asthma, where a vast compendium of genetic approaches has been used (e.g., gene-environment interactions, next-generation sequencing, or polygenic risk scores). Furthermore, the roles of the DNA methylome and histone modifications in AEs have been scarcely investigated, and microRNA findings remain to be validated in independent studies. Likewise, the most recent transcriptomic studies highlight the importance of host-airway microbiome interaction in the modulation of AEs risk. Leveraging -omics and deep-phenotyping data from sub-types or homogenous subgroups of patients will be crucial to overcome the inherent heterogeneity of AEs, and boost the identification of potential therapeutic targets and the implementation of precision medicine in clinical practice for AEs.

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“…This increase may result from ELL2 downregulation which is commonly observed in PCa whereby ELL2 expression inversely correlates with Gleason scores (121). Furthermore, BIRC3 has also been identified as a glucocorticoid receptor (GR) regulated gene (122,123), although this was in the context of bronchial and pulmonary epithelial cells. The GR is also correlated with CRPC and PCa progression (124), whereby androgens can bind the GR to activate proliferation genes due to high homology between the AR and GR (125).…”

Section: Birc3mentioning

confidence: 99%

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

et al. 2023

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Persistent androgen receptor (AR) signalling is the main driver of prostate cancer (PCa). Truncated isoforms of the AR called androgen receptor variants (AR-Vs) lacking the ligand binding domain often emerge during treatment resistance against AR pathway inhibitors such as Enzalutamide. This review discusses how AR-Vs drive a more aggressive form of PCa through the regulation of some of their target genes involved in oncogenic pathways, enabling disease progression. There is a pressing need for the development of a new generation of AR inhibitors which can repress the activity of both the full-length AR and AR-Vs, for which the knowledge of differentially expressed target genes will allow evaluation of inhibition efficacy. This review provides a detailed account of the most common variant, AR-V7, the AR-V7 regulated genes which have been experimentally validated, endeavours to understand their relevance in aggressive AR-V driven PCa and discusses the utility of the downstream protein products as potential drug targets for PCa treatment.

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Multiomics analysis identifies BIRC3 as a novel glucocorticoid response–associated gene

Cited by 9 publications

References 52 publications

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells

Differential regulation of BIRC2 and BIRC3 expression by inflammatory cytokines and glucocorticoids in pulmonary epithelial cells

Asthma Exacerbations: The Genes Behind the Scenes

A compendium of Androgen Receptor Variant 7 target genes and their role in Castration Resistant Prostate Cancer

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