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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Main Authors: Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J McDonald, David G Schatz
Format: Article
Language:English
Published: Public Library of Science (PLoS) 2014-04-01
Series:PLoS Biology
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBI
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spelling doaj-d8c75f8713464da9bd7f8ad340ca12632021-07-02T21:22:24ZengPublic 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://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBI
collection DOAJ
language English
format Article
sources DOAJ
author Jean-Marie Buerstedde
Jukka Alinikula
Hiroshi Arakawa
Jessica J McDonald
David G Schatz
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
author_facet Jean-Marie Buerstedde
Jukka Alinikula
Hiroshi Arakawa
Jessica J McDonald
David G Schatz
author_sort Jean-Marie Buerstedde
title 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_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_sort targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.
publisher Public Library of Science (PLoS)
series PLoS Biology
issn 1544-9173
1545-7885
publishDate 2014-04-01
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.
url https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBI
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AT hiroshiarakawa targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences
AT jessicajmcdonald targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences
AT davidgschatz targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences
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