Recombination may occur in the absence of transcription in the immunoglobulin heavy chain recombination centre

Author:

Oudinet Chloé1,Braikia Fatima-Zohra1,Dauba Audrey1,Khamlichi Ahmed Amine1ORCID

Affiliation:

1. Institut de Pharmacologie et de Biologie Structurale, IPBS, Université de Toulouse, CNRS, Université Paul Sabatier, 31077 Toulouse, France

Abstract

AbstractDeveloping B cells undergo V(D)J recombination to generate a vast repertoire of Ig molecules. V(D)J recombination is initiated by the RAG1/RAG2 complex in recombination centres (RCs), where gene segments become accessible to the complex. Whether transcription is the causal factor of accessibility or whether it is a side product of other processes that generate accessibility remains a controversial issue. At the IgH locus, V(D)J recombination is controlled by Eμ enhancer, which directs the transcriptional, epigenetic and recombinational events in the IgH RC. Deletion of Eμ enhancer affects both transcription and recombination, making it difficult to conclude if Eμ controls the two processes through the same or different mechanisms. By using a mouse line carrying a CpG-rich sequence upstream of Eμ enhancer and analyzing transcription and recombination at the single-cell level, we found that recombination could occur in the RC in the absence of detectable transcription, suggesting that Eμ controls transcription and recombination through distinct mechanisms. Moreover, while the normally Eμ-dependent transcription and demethylating activities were impaired, recruitment of chromatin remodeling complexes was unaffected. RAG1 was efficiently recruited, thus compensating for the defective transcription-associated recruitment of RAG2, and providing a mechanistic basis for RAG1/RAG2 assembly to initiate V(D)J recombination.

Funder

Agence Nationale de la Recherche

Institut National Du Cancer

Fondation ARC pour la Recherche sur le Cancer

Ligue Contre le Cancer

Publisher

Oxford University Press (OUP)

Subject

Genetics

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