Reversal of splicing infidelity is a pre-activation step in B cell differentiation
IntroductionB cell activation and differentiation is central to the adaptive immune response. Changes in exon usage can have major impacts on cellular signaling and differentiation but have not been systematically explored in differentiating B cells.MethodsWe analyzed exon usage and intron retention...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060114/full |
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| author | Tina M. O’Grady Melody Baddoo Samuel A. Flemington Eman Y. Ishaq Nathan A. Ungerleider Erik K. Flemington |
| author_facet | Tina M. O’Grady Melody Baddoo Samuel A. Flemington Eman Y. Ishaq Nathan A. Ungerleider Erik K. Flemington |
| author_sort | Tina M. O’Grady |
| collection | DOAJ |
| description | IntroductionB cell activation and differentiation is central to the adaptive immune response. Changes in exon usage can have major impacts on cellular signaling and differentiation but have not been systematically explored in differentiating B cells.MethodsWe analyzed exon usage and intron retention in RNA-Seq data from subsets of human B cells at various stages of differentiation, and in an in vitro laboratory model of B cell activation and differentiation (Epstein Barr virus infection).ResultsBlood naïve B cells were found to have an unusual splicing profile, with unannotated splicing events in over 30% of expressed genes. Splicing changed substantially upon naïve B cell entry into secondary lymphoid tissue and before activation, involving significant increases in exon commitment and reductions in intron retention. These changes preferentially involved short introns with weak splice sites and were likely mediated by an overall increase in splicing efficiency induced by the lymphoid environment. The majority of transcripts affected by splicing changes showed restoration of encoded conserved protein domains and/or reduced targeting to the nonsense-mediated decay pathway. Affected genes were enriched in functionally important immune cell activation pathways such as antigen-mediated signaling, cell cycle control and mRNA processing and splicing.DiscussionFunctional observations from donor B cell subsets in progressive states of differentiation and from timecourse experiments using the in vitro model suggest that these widespread changes in mRNA splicing play a role in preparing naïve B cells for the decisive step of antigen-mediated activation and differentiation. |
| first_indexed | 2024-04-13T04:36:05Z |
| format | Article |
| id | doaj.art-9ddc30d1071c41caa874aa80b3fa81b5 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-13T04:36:05Z |
| publishDate | 2022-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-9ddc30d1071c41caa874aa80b3fa81b52022-12-22T03:02:10ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-12-011310.3389/fimmu.2022.10601141060114Reversal of splicing infidelity is a pre-activation step in B cell differentiationTina M. O’Grady0Melody Baddoo1Samuel A. Flemington2Eman Y. Ishaq3Nathan A. Ungerleider4Erik K. Flemington5Department of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesTulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesDepartment of Pathology & Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United StatesIntroductionB cell activation and differentiation is central to the adaptive immune response. Changes in exon usage can have major impacts on cellular signaling and differentiation but have not been systematically explored in differentiating B cells.MethodsWe analyzed exon usage and intron retention in RNA-Seq data from subsets of human B cells at various stages of differentiation, and in an in vitro laboratory model of B cell activation and differentiation (Epstein Barr virus infection).ResultsBlood naïve B cells were found to have an unusual splicing profile, with unannotated splicing events in over 30% of expressed genes. Splicing changed substantially upon naïve B cell entry into secondary lymphoid tissue and before activation, involving significant increases in exon commitment and reductions in intron retention. These changes preferentially involved short introns with weak splice sites and were likely mediated by an overall increase in splicing efficiency induced by the lymphoid environment. The majority of transcripts affected by splicing changes showed restoration of encoded conserved protein domains and/or reduced targeting to the nonsense-mediated decay pathway. Affected genes were enriched in functionally important immune cell activation pathways such as antigen-mediated signaling, cell cycle control and mRNA processing and splicing.DiscussionFunctional observations from donor B cell subsets in progressive states of differentiation and from timecourse experiments using the in vitro model suggest that these widespread changes in mRNA splicing play a role in preparing naïve B cells for the decisive step of antigen-mediated activation and differentiation.https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060114/fulllymphocyte activationmRNAalternative splicingexon skippingnaïve B cellslymphoid tissue |
| spellingShingle | Tina M. O’Grady Melody Baddoo Samuel A. Flemington Eman Y. Ishaq Nathan A. Ungerleider Erik K. Flemington Reversal of splicing infidelity is a pre-activation step in B cell differentiation Frontiers in Immunology lymphocyte activation mRNA alternative splicing exon skipping naïve B cells lymphoid tissue |
| title | Reversal of splicing infidelity is a pre-activation step in B cell differentiation |
| title_full | Reversal of splicing infidelity is a pre-activation step in B cell differentiation |
| title_fullStr | Reversal of splicing infidelity is a pre-activation step in B cell differentiation |
| title_full_unstemmed | Reversal of splicing infidelity is a pre-activation step in B cell differentiation |
| title_short | Reversal of splicing infidelity is a pre-activation step in B cell differentiation |
| title_sort | reversal of splicing infidelity is a pre activation step in b cell differentiation |
| topic | lymphocyte activation mRNA alternative splicing exon skipping naïve B cells lymphoid tissue |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.1060114/full |
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