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Deciphering the importance of the palindromic architecture of the immunoglobulin heavy chain 3â?? regulatory region.

ABSTRACT: The IgH 3â?? regulatory region (3â??RR) controls class switch recombination (CSR) and somatic hypermutation (SHM) in B cells. The mouse 3â??RR contains four enhancer elements with hs1,2 flanked by inverted repeated sequences and the center of a 25-kb palindrome bounded by two hs3 enhancer inverted copies (hs3a and hs3b). hs4 lies downstream of the palindrome. Evolution maintained in mammals this unique palindromic arrangement suggesting that it is functionally significant. We report that deconstructing the palindromic IgH 3â??RR strongly impacts its function even when enhancers are preserved. CSR and IgH transcription appear poorly dependent from the 3â??RR architecture and are more or less preserved provided 3â??RR enhancers are present. By contrast, an â??architectural effectâ?? significantly lowers VH germline transcription, AID recruitment and SHM. In conclusion, this work indicates that the IgH 3â??RR does not simply pile up enhancer units but also optimally expose them into a functional architecture of crucial importance. RNAseq analysis of B-cell splenocytes with (S=stimulated) or without (R=resting) LPS activation from wt, delta2leftPAL, and deltaIRIS mice.

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Lebrigand

PROVIDER: E-GEOD-76359 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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RNA-SEQ on resting (R) and stimulated (S) B cells from several IgH 3'RR mutant models

Project description:We evaluated by RNA-seq obveral transcripts in B cells (resting and activated for 2 days with LPS) sorted from several KO mice models devoid of portion or all the IgH 3' Regulatory Region One RNA-seq point was realized per condition (resting or stimulated) and per genotype. Each point corresponds to a pool of equivalent number of B cells sorted from 4 animals

2016-03-02 | E-GEOD-76217 | biostudies-arrayexpress

Deciphering the importance of the palindromic architecture of the immunoglobulin heavy chain 3’ regulatory region.

Project description:The IgH 3’ regulatory region (3’RR) controls class switch recombination (CSR) and somatic hypermutation (SHM) in B cells. The mouse 3’RR contains four enhancer elements with hs1,2 flanked by inverted repeated sequences and the center of a 25-kb palindrome bounded by two hs3 enhancer inverted copies (hs3a and hs3b). hs4 lies downstream of the palindrome. Evolution maintained in mammals this unique palindromic arrangement suggesting that it is functionally significant. We report that deconstructing the palindromic IgH 3’RR strongly impacts its function even when enhancers are preserved. CSR and IgH transcription appear poorly dependent from the 3’RR architecture and are more or less preserved provided 3’RR enhancers are present. By contrast, an “architectural effect” significantly lowers VH germline transcription, AID recruitment and SHM. In conclusion, this work indicates that the IgH 3’RR does not simply pile up enhancer units but also optimally expose them into a functional architecture of crucial importance.

2016-02-08 | GSE76359 | GEO

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The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination

Project description:Class Switch Recombination (CSR) is a DNA recombination reaction that diversifies the effector component of antibody responses. CSR is initiated by activation-induced cytidine deaminase (AID), which targets transcriptionally active immunoglobulin heavy chain (Igh) switch donor and acceptor DNA. The 3’ Igh super-enhancer, 3’ Regulatory Region (3’RR), is essential for acceptor region transcription, but how this function is regulated is unknown. Here we identify the chromatin reader ZMYND8 as an essential regulator of the 3’RR and CSR. In B cells, ZMYND8 binds promoters and super-enhancers, including the 3’RR, and controls its activity by modulating the enhancer transcriptional status. In its absence, there is increased 3’RR polymerase loading, and decreased acceptor region transcription and CSR. In addition to CSR, ZMYND8 deficiency impairs somatic hypermutation (SHM) of Igh, which is also dependent on the 3’RR. Thus ZMYND8 controls Igh diversification in mature B lymphocytes by regulating the activity of the 3’ Igh super-enhancer.

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The superenhancer binding factor Med1 is broadly required for optimally expressing and hypermutating IgH genes as well as for terminating their expression through locus suicide recombination

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IgH 3'RR mutant mice

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YY1 Controls Em-3â??RR DNA Loop Formation and Immunoglobulin Heavy Chain Class Switch Recombination.

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2016-08-06 | E-GEOD-85259 | biostudies-arrayexpress

HIRA-dependent H3.3 deposition and its modification H3.3K36me3 facilitate somatic hypermutation of immunoglobulin genes by maintaining the proper chromatin state and transcription

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