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

ABSTRACT: Activation of splenic B cells induces formation of a 220kb DNA loop between Em and 3’RR enhancers in the immunoglobulin heavy chain locus (IgH). This DNA loop has been proposed to be necessary for the crucial immune diversification mechanism of IgH class switch recombination, but the factors that control its formation are unknown. We show that conditional deletion of transcription factor YY1 in primary splenic B cells results in a dramatic drop in formation of this DNA loop, as well as immunoglobulin class switch recombination. Reconstitution of YY1-deleted splenic B cells with various YY1 mutants showed that the C-terminal half of YY1 lacking the transactivation domain restored both Em-3’RR DNA loop formation as well as class switch recombination. RNA transcript analyses of YY1 conditional deleted splenic B cells suggest that YY1 does not regulate genes needed for DNA looping or CSR. Our results argue for a direct physical mechanism of YY1 mediating long-distance DNA loops and provide strong evidence of the importance of this DNA loop for class switching. Our results provide foundational mechanistic insight into a crucial immune function.

ORGANISM(S): Mus musculus

PROVIDER: GSE85259 | GEO | 2016/08/06

SECONDARY ACCESSION(S): PRJNA337963

REPOSITORIES: GEO

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

Project description:Activation of splenic B cells induces formation of a 220kb DNA loop between Em and 3â??RR enhancers in the immunoglobulin heavy chain locus (IgH). This DNA loop has been proposed to be necessary for the crucial immune diversification mechanism of IgH class switch recombination, but the factors that control its formation are unknown. We show that conditional deletion of transcription factor YY1 in primary splenic B cells results in a dramatic drop in formation of this DNA loop, as well as immunoglobulin class switch recombination. Reconstitution of YY1-deleted splenic B cells with various YY1 mutants showed that the C-terminal half of YY1 lacking the transactivation domain restored both Em-3â??RR DNA loop formation as well as class switch recombination. RNA transcript analyses of YY1 conditional deleted splenic B cells suggest that YY1 does not regulate genes needed for DNA looping or CSR. Our results argue for a direct physical mechanism of YY1 mediating long-distance DNA loops and provide strong evidence of the importance of this DNA loop for class switching. Our results provide foundational mechanistic insight into a crucial immune function. Follicular B cells were isolated from the spleens of three C57Bl/6 yy1 fl/fl mice. For each spleen, half the cells received mock treatment and half received TATCRE. The 6 samples were then grown in RPMI medium along with LPS, Il4, OPI, and 20% FBS for 72 hours. The 6 groups of cells were lysed and RNA was isolated for library preparation. Expression differences between Mock and TATCRE treated cells were determined to understand the role of yy1 in B cell class switching.

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

Mus musculus

Project description:YY1 Controls Em-3’RR DNA Loop Formation and Immunoglobulin Heavy Chain Class Switch Recombination.

| PRJNA337963 | ENA

YY1 Control of Mitochondrial-Related Genes does not Account for Regulation of Immunoglobulin Class Switch Recombination

Project description:Immunoglobulin class switch recombination (CSR) occurs in activated B cells with increased mitochondrial mass and membrane potential. Transcription factor YY1 is critical for CSR and for formation of the DNA loops involved in this process. We therefore sought to determine if YY1 knockout impacts mitochondrial gene expression and mitochondrial function in murine splenic B cells, providing a potential mechanism for regulating CSR. We identified numerous genes in splenic B cells differentially regulated when cells are induced to undergo CSR. YY1 conditional knockout caused differential expression of 1129 genes, with 59 being mitochondrial-related genes. ChIP-seq analyses showed YY1 directly bound to nearly half of these mitochondrial-related genes. Surprisingly, at the time when YY1 knockout dramatically reduces DNA loop formation and CSR, mitochondrial mass and membrane potential were not significantly impacted, nor was there a significant change in mitochondrial oxygen consumption, extracellular acidification rate, or mitochondrial complex I or IV activities. Our results indicate that YY1 regulates numerous mitochondrial-related genes in splenic B cells, but this does not account for the impact of YY1 on CSR, or long-distance DNA loop formation.

2020-02-13 | GSE145161 | GEO

Transcriptoma analysis of B splenocytes of 3'RR-deficient mice and wt mice

Project description:The IgH 3' regulatory region (3'RR) controls class switch recombination and somatic hypermutation in mice. Similar numbers of B cells are found in spleen of 3'RR-deficient mice and wt mice. We compare their transcriptoma in order to find differences in their maturation status. B splenocytes from four wt mice and four 3'RR-deficient mice are investigated. Splenic B cells are purified with anti-B220-coupled beads.

2014-01-15 | E-GEOD-45230 | biostudies-arrayexpress

Senataxin and RNase H2 act redundantly to suppress genome instability during class switch recombination

Project description:Class switch recombination generates antibody distinct isotypes critical to a robust adaptive immune system and defects are associated with auto-immune disorders and lymphomagenesis. Transcription is required during class switch to recruit the cytidine deaminase AID—an essential step for the formation of DNA doublestrand breaks—and strongly induces the formation of R loops within the immunoglobulin heavy chain locus. However, the impact of R loops on double-strand break formation and repair during class switch recombination remains unclear. Here we report that cells lacking two enzymes involved in R loop removal— Senataxin and RNase H2—exhibit increased R loop formation and genome instability at the immunoglobulin heavy chain locus without impacting class switch recombination efficiency, transcriptional activity, or AID recruitment. Senataxin and RNase H2-deficient cells also exhibit increased insertion mutations at switch junctions, a hallmark of alternative end joining. Importantly, these phenotypes were not observed in cells lacking Senataxin or RNase H2B alone. We propose that Senataxin acts redundantly with RNase H2 to mediate timely R loop removal, promoting efficient repair while suppressing AID-dependent genome instability and insertional mutagenesis.

2022-12-14 | GSE201210 | GEO

A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination [Micro-C]

Project description:Antibody class switch recombination (CSR) requires the ligation of DNA breaks in transcribed and juxtaposed donor and acceptor switch (S) sequences (S-S synapsis) spaced 50-200 kb apart within the immunoglobulin heavy chain locus (Igh). CSR is believed to occur via the association of active S regions with the 3’ regulatory region (3’RR) super-enhancer thereby coupling transcription with S-S synapsis. Here, we map the multi-way interactome underlying CSR using Tri-C. Surprisingly, S-S synapsis is strongly associated with the 3` CTCF binding element (3`CBE), but not the 3’RR, a finding also confirmed by Micro-C measurements. Instead, the 3’RR forms a self-interacting domain independently engaging with Igh genes. Additionally, transcription at acceptor S regions creates a topological barrier that insulates S-S synapsis from loop extrusion complexes. Thus, Igh gene activation and S-S synapsis occur via distinct topological states created by the interaction between transcription and the loop extrusion machinery.

2023-01-20 | GSE198181 | GEO

A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination [PRO-seq]

2023-01-20 | GSE198180 | GEO

A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination [Tri-C]

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A de novo transcription-dependent TAD boundary underpins critical multiway interactions during antibody class switch recombination [ChIP-Seq]

2023-01-20 | GSE198176 | GEO

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.

2018-10-04 | GSE118794 | GEO

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