Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F20%3A00559752" target="_blank" >RIV/68378050:_____/20:00559752 - isvavai.cz</a>

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/10.1002/eji.201948357" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1002/eji.201948357</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/eji.201948357" target="_blank" >10.1002/eji.201948357</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

Popis výsledku v původním jazyce

Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer-like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E-box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Ig lambda enhancer and/or the IgH intronic enhancer (E mu) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in E mu and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of E mu mutants. Our results provide novel insights into trans-acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.

Název v anglickém jazyce

Transcription factor binding at Ig enhancers is linked to somatic hypermutation targeting

Popis výsledku anglicky

Secondary diversification of the Ig repertoire occurs through somatic hypermutation (SHM), gene conversion (GCV), and class switch recombination (CSR)-three processes that are initiated by activation-induced cytidine deaminase (AID). AID targets Ig genes at orders of magnitude higher than the rest of the genome, but the basis for this specificity is poorly understood. We have previously demonstrated that enhancers and enhancer-like sequences from Ig genes are capable of stimulating SHM of neighboring genes in a capacity distinct from their roles in increasing transcription. Here, we use an in vitro proteomics approach to identify E-box, MEF2, Ets, and Ikaros transcription factor family members as potential binders of these enhancers. ChIP assays in the hypermutating Ramos B cell line confirmed that many of these factors bound the endogenous Ig lambda enhancer and/or the IgH intronic enhancer (E mu) in vivo. Further investigation using SHM reporter assays identified binding sites for E2A and MEF2B in E mu and demonstrated an association between loss of factor binding and decreases in the SHM stimulating activity of E mu mutants. Our results provide novel insights into trans-acting factors that dictate SHM targeting and link their activity to specific DNA binding sites within Ig enhancers.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30102 - Immunology

Projekt

<a href="/cs/project/GA15-24776S" target="_blank" >GA15-24776S: Chybné cílení somatických hypermutací a jeho vliv na nestabilitu genomu B lymfocytů</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Immunology

ISSN

0014-2980

e-ISSN

1521-4141

Svazek periodika

50

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

16

Strana od-do

380-395

Kód UT WoS článku

000503430500001

EID výsledku v databázi Scopus

—