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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Autores principales:	Jean-Marie Buerstedde, Jukka Alinikula, Hiroshi Arakawa, Jessica J McDonald, David G Schatz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d8c75f8713464da9bd7f8ad340ca1263
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spelling	oai:doaj.org-article:d8c75f8713464da9bd7f8ad340ca12632021-11-18T05:37:30ZTargeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.1544-91731545-788510.1371/journal.pbio.1001831https://doaj.org/article/d8c75f8713464da9bd7f8ad340ca12632014-04-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24691034/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Somatic 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.Jean-Marie BuersteddeJukka AlinikulaHiroshi ArakawaJessica J McDonaldDavid G SchatzPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 12, Iss 4, p e1001831 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jean-Marie Buerstedde Jukka Alinikula Hiroshi Arakawa Jessica J McDonald David G Schatz Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.
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
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
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)
publishDate	2014
url	https://doaj.org/article/d8c75f8713464da9bd7f8ad340ca1263
work_keys_str_mv	AT jeanmariebuerstedde targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences AT jukkaalinikula targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences AT hiroshiarakawa targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences AT jessicajmcdonald targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences AT davidgschatz targetingofsomatichypermutationbyimmunoglobulinenhancerandenhancerlikesequences
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Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.

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