The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells
Type 1 diabetes (T1D) is characterized by a prolonged autoimmune attack resulting in the massive loss of insulin-producing beta cells. The initiation and progression of T1D depends on a complex interaction between genetic, immunological and environmental factors. Epidemiological, experimental and cl...
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Frontiers Media S.A.
2024-12-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1501061/full |
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| author | Maressa Fernandes Bonfim Camille Aitchedji Flore Van Goethem Lionel Sauvage Thibault Poinsot Emilie Calonne Rachel Deplus François Fuks Decio L. Eizirik Anne Op de Beeck Anne Op de Beeck |
| author_facet | Maressa Fernandes Bonfim Camille Aitchedji Flore Van Goethem Lionel Sauvage Thibault Poinsot Emilie Calonne Rachel Deplus François Fuks Decio L. Eizirik Anne Op de Beeck Anne Op de Beeck |
| author_sort | Maressa Fernandes Bonfim |
| collection | DOAJ |
| description | Type 1 diabetes (T1D) is characterized by a prolonged autoimmune attack resulting in the massive loss of insulin-producing beta cells. The initiation and progression of T1D depends on a complex interaction between genetic, immunological and environmental factors. Epidemiological, experimental and clinical evidence suggest a link between viral infections, particularly Coxsackievirus type B (CVB), and T1D development. Specifically, infections by the CVB serotype 1 (CVB1) contribute to the triggering of autoimmunity against beta cells in genetically predisposed individuals, and prolonged and probably non-lytic infections by CVB are associated with the development of T1D. However, the molecular mechanisms underlying CVB1 replication and establishing persistent infections in human pancreatic beta cells remain poorly understood. Here we show that the N6-methyladenosine (m6A) RNA epigenetic modification machinery regulates CVB1 amplification in the human beta cells. Using small interfering RNA (siRNA) targeting m6A writers and erasers, we observed that downregulation of m6A writers increases CVB1 amplification, while the downregulation of m6A erasers decreases it. Notably, the inhibition of Fat Mass and Obesity-associated protein (FTO), a key m6A eraser, reduced by 95% the production of infectious CVB1 in both human insulin-producing EndoC-βH1 cells and in induced pluripotent stem cell (iPSC)-derived islets. The FTO inhibitor reduced CVB1 expression within 6 h post-infection, suggesting a direct regulation of the CVB1 genome by m6A modification. Furthermore, in the absence of viral replication, FTO inhibition also decreased the translation of the incoming CVB1 genome, indicating that m6A plays a critical role in the initial stages of viral RNA translation. In addition, modulation of the m6A machinery affected the type I interferon response after poly-IC transfection, a mimic of RNA virus replication, but did not affect the cellular antiviral response in CVB1-infected cells. Altogether, these observations suggest that m6A directly affects CVB1 production. Our study provides the first evidence that the m6A epigenetic modification machinery controls CVB amplification in human pancreatic beta cells. This suggests that the m6A machinery is a potential target to control CVB infection in T1D and raises the possibility of an epigenetic control in the establishment of persistent CVB infections observed in the pancreas in individuals with type 1 diabetes. |
| format | Article |
| id | doaj-art-66a4b03ae5b444c4b69e24c4f43a39e2 |
| institution | Kabale University |
| issn | 1664-302X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Microbiology |
| spelling | doaj-art-66a4b03ae5b444c4b69e24c4f43a39e22024-12-18T06:43:56ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2024-12-011510.3389/fmicb.2024.15010611501061The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cellsMaressa Fernandes Bonfim0Camille Aitchedji1Flore Van Goethem2Lionel Sauvage3Thibault Poinsot4Emilie Calonne5Rachel Deplus6François Fuks7Decio L. Eizirik8Anne Op de Beeck9Anne Op de Beeck10ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumThe Laboratory of Cancer Epigenetics, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumThe Laboratory of Cancer Epigenetics, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumThe Laboratory of Cancer Epigenetics, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, BelgiumLaboratory of Microbiology, European Plotkin Institute for Vaccinology, Université Libre de Bruxelles, Brussels, BelgiumType 1 diabetes (T1D) is characterized by a prolonged autoimmune attack resulting in the massive loss of insulin-producing beta cells. The initiation and progression of T1D depends on a complex interaction between genetic, immunological and environmental factors. Epidemiological, experimental and clinical evidence suggest a link between viral infections, particularly Coxsackievirus type B (CVB), and T1D development. Specifically, infections by the CVB serotype 1 (CVB1) contribute to the triggering of autoimmunity against beta cells in genetically predisposed individuals, and prolonged and probably non-lytic infections by CVB are associated with the development of T1D. However, the molecular mechanisms underlying CVB1 replication and establishing persistent infections in human pancreatic beta cells remain poorly understood. Here we show that the N6-methyladenosine (m6A) RNA epigenetic modification machinery regulates CVB1 amplification in the human beta cells. Using small interfering RNA (siRNA) targeting m6A writers and erasers, we observed that downregulation of m6A writers increases CVB1 amplification, while the downregulation of m6A erasers decreases it. Notably, the inhibition of Fat Mass and Obesity-associated protein (FTO), a key m6A eraser, reduced by 95% the production of infectious CVB1 in both human insulin-producing EndoC-βH1 cells and in induced pluripotent stem cell (iPSC)-derived islets. The FTO inhibitor reduced CVB1 expression within 6 h post-infection, suggesting a direct regulation of the CVB1 genome by m6A modification. Furthermore, in the absence of viral replication, FTO inhibition also decreased the translation of the incoming CVB1 genome, indicating that m6A plays a critical role in the initial stages of viral RNA translation. In addition, modulation of the m6A machinery affected the type I interferon response after poly-IC transfection, a mimic of RNA virus replication, but did not affect the cellular antiviral response in CVB1-infected cells. Altogether, these observations suggest that m6A directly affects CVB1 production. Our study provides the first evidence that the m6A epigenetic modification machinery controls CVB amplification in human pancreatic beta cells. This suggests that the m6A machinery is a potential target to control CVB infection in T1D and raises the possibility of an epigenetic control in the establishment of persistent CVB infections observed in the pancreas in individuals with type 1 diabetes.https://www.frontiersin.org/articles/10.3389/fmicb.2024.1501061/fullm6Acoxsackieviruspancreatic beta celltype 1 diabetesepigenetic regulation |
| spellingShingle | Maressa Fernandes Bonfim Camille Aitchedji Flore Van Goethem Lionel Sauvage Thibault Poinsot Emilie Calonne Rachel Deplus François Fuks Decio L. Eizirik Anne Op de Beeck Anne Op de Beeck The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells Frontiers in Microbiology m6A coxsackievirus pancreatic beta cell type 1 diabetes epigenetic regulation |
| title | The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells |
| title_full | The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells |
| title_fullStr | The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells |
| title_full_unstemmed | The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells |
| title_short | The N6-methyladenosine RNA epigenetic modification modulates the amplification of coxsackievirus B1 in human pancreatic beta cells |
| title_sort | n6 methyladenosine rna epigenetic modification modulates the amplification of coxsackievirus b1 in human pancreatic beta cells |
| topic | m6A coxsackievirus pancreatic beta cell type 1 diabetes epigenetic regulation |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2024.1501061/full |
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