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Uncoupling splicing from transcription using antisense oligonucleotides reveals a dual role for I exon donor splice sites in antibody class switching

Anne Marchalot, Mohamad Omar Ashi, Jean-Marie Lambert, Nivine Srour, View ORCID ProfileLaurent Delpy, Soazig Le Pennec
doi: https://doi.org/10.1101/850867
Anne Marchalot
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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Mohamad Omar Ashi
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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Jean-Marie Lambert
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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Nivine Srour
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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Laurent Delpy
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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  • ORCID record for Laurent Delpy
  • For correspondence: soazig.le-pennec@unilim.fr laurent.delpy@unilim.fr
Soazig Le Pennec
aUnité Mixte de Recherche CNRS 7276 - INSERM 1262 - Université de Limoges, Limoges, France
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  • For correspondence: soazig.le-pennec@unilim.fr laurent.delpy@unilim.fr
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ABSTRACT

Class switch recombination (CSR) changes antibody isotype by replacing Cμ constant exons with different constant exons located downstream on the immunoglobulin heavy (IgH) locus. During CSR, transcription through specific switch (S) regions and processing of noncoding germline transcripts (GLTs) are essential for the targeting of Activation-Induced cytidine Deaminase (AID). While CSR to IgG1 is abolished in mice lacking Iγ1 exon donor splice site (dss), many questions remain regarding the importance of I exon dss recognition in CSR. To further clarify the role of I exon dss in CSR, we first evaluated RNA polymerase II (RNA pol II) loading and chromatin accessibility in S regions after activation of mouse B cells lacking Iγ1 dss. We found that deletion of Iγ1 dss markedly reduced RNA pol II pausing and active chromatin marks in the Sγ1 region. We then challenged the post-transcriptional function of I exon dss in CSR by using antisense oligonucleotides (ASO) masking I exon dss on GLTs. Treatment of stimulated B cells with an ASO targeting Iγ1 dss, in the acceptor Sγ1 region, or Iμ dss, in the donor Sμ region, did not decrease germline transcription but strongly inhibited constitutive splicing and CSR to IgG1. Altogether, this study reveals that the recognition of I exon dss first supports RNA pol II pausing and the opening of chromatin in targeted S regions and that GLTs splicing events using constitutive I exon dss appear mandatory for the later steps of CSR, most likely by guiding AID to S regions.

Footnotes

  • This work was supported by grants from Fondation ARC (PJA 20161204724), INCa (PLBIO15-256), ANR (2017-CE15-0024-01), Ligue Contre le Cancer (CD87, CD19, CD23), and Fondation Française pour la Recherche contre le Myélome et les Gammapathies monoclonales (FFRMG).

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted November 22, 2019.
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Uncoupling splicing from transcription using antisense oligonucleotides reveals a dual role for I exon donor splice sites in antibody class switching
Anne Marchalot, Mohamad Omar Ashi, Jean-Marie Lambert, Nivine Srour, Laurent Delpy, Soazig Le Pennec
bioRxiv 850867; doi: https://doi.org/10.1101/850867
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Uncoupling splicing from transcription using antisense oligonucleotides reveals a dual role for I exon donor splice sites in antibody class switching
Anne Marchalot, Mohamad Omar Ashi, Jean-Marie Lambert, Nivine Srour, Laurent Delpy, Soazig Le Pennec
bioRxiv 850867; doi: https://doi.org/10.1101/850867

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