Dataset Information

The Magnitude of IFN-? Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

ABSTRACT: Interferon gamma (IFN-?), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defense. Insertion of a polyA signal ablated the Ifng-as1 full-length transcript and impaired host defense, while allowing proper chromatin structure. Transient knockdown of Ifng-as1 also reduced IFN-? production. In humans, discordant expression of IFNG and IFNG-AS1 was evident in memory T cells, with high expression of this long non-coding RNA (lncRNA) and low expression of the cytokine. These results establish Ifng-as1 as an important regulator of Ifng expression, as a DNA element and transcribed RNA, involved in dynamic and cell state-specific responses to infection.

SUBMITTER: Petermann F

PROVIDER: S-EPMC6754279 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

Petermann Franziska F Pękowska Aleksandra A Johnson Catrina A CA Jankovic Dragana D Shih Han-Yu HY Jiang Kan K Hudson William H WH Brooks Stephen R SR Sun Hong-Wei HW Villarino Alejandro V AV Yao Chen C Singleton Kentner K Akondy Rama S RS Kanno Yuka Y Sher Alan A Casellas Rafael R Ahmed Rafi R O'Shea John J JJ

Molecular cell 20190731 6

Interferon gamma (IFN-γ), critical for host defense and tumor surveillance, requires tight control of its expression. Multiple cis-regulatory elements exist around Ifng along with a non-coding transcript, Ifng-as1 (also termed NeST). Here, we describe two genetic models generated to dissect the molecular functions of this locus and its RNA product. DNA deletion within the Ifng-as1 locus disrupted chromatin organization of the extended Ifng locus, impaired Ifng response, and compromised host defe ...[more]

PMID: 31377117

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Project description:Background/aim: IFNG-AS1 is a long noncoding RNA that works as an enhancer for the Interferon-gamma (IFN-γ) transcript. GAS5 (growth arrest-specific 5) is a lncRNA that is associated with glucocorticoid resistance. Aberrant expressions of IFNG-AS1 and GAS5 are directly linked to numerous autoimmune disorders but their levels in childhood ITP are still obscure. This study aims to elucidate expressions of target lncRNAs in childhood ITP and their association with pathophysiology and clinical features of the disease as well as their association with types and treatment responses. Method: The fold changes of target lncRNAs in blood samples from children with ITP and healthy controls were analyzed using quantitative real-time PCR (qRT-PCR). Results: There were overexpressed lncRNAs IFNG-AS1 and GAS5 in serum of childhood ITP patients [(median (IQR) = 3.08 (0.2-22.39) and 4.19 (0.9-16.91) respectively, Also, significant higher IFNG-AS1 and GAS5 (p < 0.05) were present in persistent ITP (3-12 months) [ median (IQR) = 4.58 (0.31-22.39) and 3.77 (0.87-12.36) respectively] or chronic ITP (>12 months) [ median (IQR) = 5.6 (0.25-12.59) and 5.61 (1.15-16.91) respectively] when compared to newly diagnosed <3 months patients [IFNG-AS1 median (IQR) = 1.21 (0.2-8.95), and GAS5 median (IQR) = 1.07 (0.09-3.55)]. Also, significant higher lncRNAs IFNG-AS1 and GAS5 were present in patients with partial response to treatment [IFNG-AS1 median (IQR) = 4.15 (0.94-19.25), and GAS5 (median (IQR) = 4.25 (0.81-16.91)] or non-response [IFNG-AS1 median (IQR) = 4.19 (1.25-22.39) and GAS5 median (IQR) = 5.11 (2.34-15.27)] when compared to patients who completely responded to treatment (IFNG-AS1 median (IQR) = 2.09 (0.2-14.58) and GAS5 (median (IQR) = 2.51 (0.09-10.33). In addition, following therapy, the expressions of IFNG-AS1 and GAS5 are significantly negatively correlated with platelet count. Conclusion: Findings suggest that lncRNAs IFNG-AS1 and GAS5 are novel diagnostic and prognostic genetic markers for childhood ITP that can aid in a precise prediction of the disease's progress at the time of diagnosis and could be a useful tool for treatment planning.

Project description:A diversity of arthropods (myrmecophiles) thrives within ant nests, many of them unmolested though some, such as the specialized Eucharitidae parasitoids, may cause direct damage to their hosts. Ants are known to discriminate between nestmates and non-nestmates, but whether they recognize the strength of a threat and their capacity to adjust their behavior accordingly have not been fully explored. We aimed to determine whether Ectatomma tuberculatum ants exhibited specific behavioral responses to potential or actual intruders posing different threats to the host colony and to contribute to an understanding of complex ant-eucharitid interactions. Behavioral responses differed significantly according to intruder type. Ants evicted intruders that represented a threat to the colony's health (dead ants) or were not suitable as prey items (filter paper, eucharitid parasitoid wasps, non myrmecophilous adult weevils), but killed potential prey (weevil larvae, termites). The timing of detection was in accordance with the nature and size of the intruder: corpses (a potential source of contamination) were detected faster than any other intruder and transported to the refuse piles within 15 min. The structure and complexity of behavioral sequences differed among those intruders that were discarded. Workers not only recognized and discriminated between several distinct intruders but also adjusted their behavior to the type of intruder encountered. Our results confirm the previously documented recognition capabilities of E. tuberculatum workers and reveal a very fine-tuned intruder discrimination response. Colony-level prophylactic and hygienic behavioral responses through effective removal of inedible intruders appears to be the most general and flexible form of defense in ants against a diverse array of intruders. However, this generalized response to both potentially lethal and harmless intruders might have driven the evolution of ant-eucharitid interactions, opening a window for parasitoid attack and allowing adult parasitoid wasps to quickly leave the natal nest unharmed.

Dataset Information

The Magnitude of IFN-? Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

Publications

The Magnitude of IFN-γ Responses Is Fine-Tuned by DNA Architecture and the Non-coding Transcript of Ifng-as1.

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