The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

The lung contains numerous specialized cell-types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a first comprehensive topographic atlas of early human lung development. We report 83 cell states, several spatially-resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated scRNA-Seq and spatial transcriptomics into a web-based, open platform for interactive exploration. To illustrate the utility of our approach we show distinct states of secretory and neuroendocrine cells, largely overlapping with the programs activated either during lung fibrosis or small cell lung cancer progression. We define the origin of uncharacterized airway fibroblasts associated with airway smooth muscle in bronchovascular bundles, and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

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“…5N). We found the anti-apoptotic factors BCL2 (Singh et al, 2019), CITED2 (Mattes et al, 2017) and IRF2BP2 (Pastor et al, 2021) (Suppl. Fig.…”

Section: Resultsmentioning

confidence: 93%

Developmental origins of cell heterogeneity in the human lung

Sountoulidis

Salas

Braun

et al. 2022

Preprint

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“…IRF2BP2, a novel transcriptional cofactor, has been shown as an oncogene or tumor suppressor partly depending on the cellular context. 32,33 It has been described that gene fusion involving the IRF2BP2, such as IRF2BP2-RARA, was present in leukemia patients. 34,35 In solid tumors, IRF2BP2 was originally identified as a tumor suppressor.…”

Section: Discussionmentioning

confidence: 99%

IRF2BP2 drives lymphatic metastasis in OSCC cells by elevating mitochondrial fission‐dependent fatty acid oxidation

Pang,

Li,

Shi

et al. 2023

Molecular Carcinogenesis

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Lymph node metastasis (LNM) is a major determinant for the poor outcome of oral squamous cell carcinoma (OSCC). Interferon regulatory factor 2 binding protein 2 (IRF2BP2) has been reported to modulate the development and progression of several types of cancers, while its role in OSCC with LNM has not been reported yet. The expression of IRF2BP2 and its association with LNM were evaluated by immunohistochemistry and qualitative reverse transcription polymerase chain reaction in clinically collected OSCC tissues. Then, loss‐of‐function and rescue assays were conducted to identify the role of IRF2BP2‐mediated fatty acid oxidation (FAO) in the invasion, lymphoinvasion, and epithelial–mesenchymal transition (EMT) in OSCC cells. Importantly, confocal microscope, transmission electron microscope, immunofluorescence, and Western blot were applied to identify the involvement of mitochondrial fission in IRF2BP2‐regulated FAO. Lastly, the in vivo models were established to evaluate the role of IRF2BP2 in OSCC. IRF2BP2 overexpression has been associated with LNM in OSCC, whose knockdown inhibited invasion, lymphoinvasion, and EMT of OSCC cells, as well as retarded FAO rate with CPT1A downregulation. And CPT1A overexpression rescued invasion, lymphoinvasion, and induced EMT in IRF2BP2‐silenced OSCC cells. Mechanically, IRF2BP2 accelerated mitochondrial fission by contributing to Drp1 S616 phosphorylation and mitochondrial localization, resulting in the upregulation of CPT1A. In addition, IRF2BP2 knockdown significantly inhibited tumor growth and LNM in vivo. The highly expressed IRF2BP2 may induce the phosphorylation and mitochondrial translocation of Drp1 to activate mitochondrial fission, which upregulated CPT1A expression and FAO rate, resulting in LNM in OSCC. This highlighted a potential therapeutic vulnerability for the treatment of LNM+ OSCC via targeting IRF2BP2‐FAO.

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“…This change results in formation of a double-stranded RNA construct that alters IRF2BP2 expression. Decreased expression of IRF2BP2 would result in increased expression of the transcription factor IRF2 and altered expression of type I interferons such as IFNA and IFNB ( Taniguchi et al, 2001 ; Ramalho-Oliveira et al, 2019 ; Pastor et al, 2021 ). The findings of Demars et al (2017) are consistent with our observations; together they suggest that a high level of type I IFN signaling results in a woolly phenotype and a low level of type I IFN signaling results in a hairy phenotype.…”

Section: Discussionmentioning

confidence: 99%

Development and characterization of type I interferon receptor knockout sheep: A model for viral immunology and reproductive signaling

et al. 2022

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Type I interferons (IFNs) initiate immune responses to viral infections. Their effects are mediated by the type I IFN receptor, IFNAR, comprised of two subunits: IFNAR1 and IFNAR2. One or both chains of the sheep IFNAR were disrupted in fetal fibroblast lines using CRISPR/Cas9 and 12 lambs were produced by somatic cell nuclear transfer (SCNT). Quantitative reverse transcription-polymerase chain reaction for IFN-stimulated gene expression showed that IFNAR deficient sheep fail to respond to IFN-alpha. Furthermore, fibroblast cells from an IFNAR2−/− fetus supported significantly higher levels of Zika virus (ZIKV) replication than wild-type fetal fibroblast cells. Although many lambs have died from SCNT related problems or infections, one fertile IFNAR2−/− ram lived to over 4 years of age, remained healthy, and produced more than 80 offspring. Interestingly, ZIKV infection studies failed to demonstrate a high level of susceptibility. Presumably, these sheep compensated for a lack of type I IFN signaling using the type II, IFN-gamma and type III, IFN-lambda pathways. These sheep constitute a unique model for studying the pathogenesis of viral infection. Historical data supports the concept that ruminants utilize a novel type I IFN, IFN-tau, for pregnancy recognition. Consequently, IFNAR deficient ewes are likely to be infertile, making IFNAR knockout sheep a valuable model for studying pregnancy recognition. A breeding herd of 32 IFNAR2+/− ewes, which are fertile, has been developed for production of IFNAR2−/− sheep for both infection and reproduction studies.

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The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

Cited by 14 publications

References 50 publications

Developmental origins of cell heterogeneity in the human lung

Developmental origins of cell heterogeneity in the human lung

IRF2BP2 drives lymphatic metastasis in OSCC cells by elevating mitochondrial fission‐dependent fatty acid oxidation

Development and characterization of type I interferon receptor knockout sheep: A model for viral immunology and reproductive signaling

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