G900 Region In Th2 Differentiation May Have Significant Implications in Asthma, Other Conditions

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Findings from a study published in Proceedings of the National Academy of Sciences, USA demonstrate that the mouse gene region that corresponds to the human G900 region plays a significant role in Type-2 helper T (Th2) cell differentiation, enhancing allergic airway inflammation. The gene region G900 is located close to the GATA3 gene and is currently being investigated for its role in the asthma inflammation pathway.^1,2

The authors note that, in humans, there are specific gene sequences called enhancers that elevate the expression of GATA3 genes, and prior research shows that by controlling the production, enhancers influence the development of Th2 and group-2 innate lymphoid cells (ILC2s). For this study, the investigators examined the roles of asthma-associated GATA3 enhancer region in experimental allergic airway inflammation by evaluating correlations between GATA3 expression and the activation of the human G900 region by flow cytometry and datasets of chromatin immunoprecipitation sequencing. Mice with a deletion of the murine homologous region to hG900 (mG900KO) were evaluated in the study, and these “knockout mice” were exposed to allergens, such as dust mites and papain.^1,2

“Multiple genome-wide association studies have aimed to elucidate the underlying biology and predict susceptibility to asthma. The importance of single nucleotide polymorphisms [SNPs] within the 10p14 locus has been indicated in several independent studies, not only in asthma susceptibility but also in a broad spectrum of allergic diseases, including allergic rhinitis, atopic dermatitis, and eosinophilic granulomatosis with polyangiitis,” said lead researcher Hiroshi Nakajima MD, PhD, professor at the Graduate School of Medicine, Chiba University, in a news release.¹

The findings demonstrate that there is a significant role of murine homologous region of human asthma-associated SNPs-enriched region in vivo differentiation of Th2 cells, and the mG900 region promotes interactions between GATA3-TSS and several enhancers in Th2 cells. Additionally, the mG900 region was activated in lung CD4+ T cells that were isolated from mice with HDM-induced allergic airway inflammation, but it was not in lung CD4+ T cells in control mice. Further, cultured Th2 cells also showed strong mG900 activation.²

The mG900KO mice produced a reduced inflammatory response compared with controls who had intact mG900 following exposure to house dust mites. Additionally, the investigators also observed a suppression of Th2 differentiation in mG900KO mice compared with controls.^1,2

“One aspect we elucidate in our study is the role of the murine G900 region in Th2 differentiation and allergic airway inflammation. This region, homologous to the human G900 region associated with asthma, is shown to be essential for in vivo Th2 cell differentiation and allergic responses, particularly in the context of house dust mite-induced allergic airway inflammation,” said Nakajima in the news release. “Furthermore, we have demonstrated that this G900 region is crucial for optimizing the 3-dimensional chromatin structure near GATA3 in Th2 cells.”¹

The investigators note that the findings may have wide-ranging implications for the asthma care space in addition to possible therapeutic interventions for other allergic diseases, despite the reason behind this currently being unknown. They are hopeful that in the future, methods that regulate Th2 differentiation and function via the pharmacological restriction of GATA3 enhancers—such as G900—may be significant in reducing exaggerated immune responses underlying allergic reactions. Further, the investigators urge that the exploration of the activation within human and murine G900 regions can be the key to understanding how Th2 cells develop in vivo.^1,2

“By identifying and understanding critical genetic regions that regulate immune responses, such as the mG900 region, it may be possible to develop precision medicine approaches tailored to individual genetic profiles. This could lead to more effective and personalized treatments, reducing the incidence and severity of allergic reactions and improving the quality of life for individuals suffering from these conditions,” concluded Nakajima in the news release.¹

References

1. Chiba University. Study elucidates role of “G900” gene enhancers in asthma-associated inflammation. News release. June 24, 2024. Accessed July 10, 2024. https://www.eurekalert.org/news-releases/1048762

2. Kumagai, T, Iwata, A, Furuya, H, et al. A distal enhancer of GATA3 regulates Th2 differentiation and allergic inflammation. PNAS. 2024;121(27):e2320727121. Doi:10.1073/pnas.2320727121