Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.
Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target s...
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| Language: | English |
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Public Library of Science (PLoS)
2014-04-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001831&type=printable |
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| author | Jean-Marie Buerstedde Jukka Alinikula Hiroshi Arakawa Jessica J McDonald David G Schatz |
| author_facet | Jean-Marie Buerstedde Jukka Alinikula Hiroshi Arakawa Jessica J McDonald David G Schatz |
| author_sort | Jean-Marie Buerstedde |
| collection | DOAJ |
| description | Somatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites--known to be important for the transcriptional role of Ig enhancers--impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units. |
| format | Article |
| id | doaj-art-d8c75f8713464da9bd7f8ad340ca1263 |
| institution | OA Journals |
| issn | 1544-9173 1545-7885 |
| language | English |
| publishDate | 2014-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj-art-d8c75f8713464da9bd7f8ad340ca12632025-08-20T02:15:24ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852014-04-01124e100183110.1371/journal.pbio.1001831Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.Jean-Marie BuersteddeJukka AlinikulaHiroshi ArakawaJessica J McDonaldDavid G SchatzSomatic hypermutation (SH) generates point mutations within rearranged immunoglobulin (Ig) genes of activated B cells, providing genetic diversity for the affinity maturation of antibodies. SH requires the activation-induced cytidine deaminase (AID) protein and transcription of the mutation target sequence, but how the Ig gene specificity of mutations is achieved has remained elusive. We show here using a sensitive and carefully controlled assay that the Ig enhancers strongly activate SH in neighboring genes even though their stimulation of transcription is negligible. Mutations in certain E-box, NFκB, MEF2, or Ets family binding sites--known to be important for the transcriptional role of Ig enhancers--impair or abolish the activity. Full activation of SH typically requires a combination of multiple Ig enhancer and enhancer-like elements. The mechanism is evolutionarily conserved, as mammalian Ig lambda and Ig heavy chain intron enhancers efficiently stimulate hypermutation in chicken cells. Our results demonstrate a novel regulatory function for Ig enhancers, indicating that they either recruit AID or alter the accessibility of the nearby transcription units.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001831&type=printable |
| spellingShingle | Jean-Marie Buerstedde Jukka Alinikula Hiroshi Arakawa Jessica J McDonald David G Schatz Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. PLoS Biology |
| title | Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. |
| title_full | Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. |
| title_fullStr | Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. |
| title_full_unstemmed | Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. |
| title_short | Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences. |
| title_sort | targeting of somatic hypermutation by immunoglobulin enhancer and enhancer like sequences |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.1001831&type=printable |
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