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Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [ChIP-Seq]

ABSTRACT: Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [ChIP-Seq]

PROVIDER: PRJNA746968 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15150470.fastq.gz	Fastqsanger.gz
	SRR15150471.fastq.gz	Fastqsanger.gz
	SRR15150472.fastq.gz	Fastqsanger.gz
	SRR15150473.fastq.gz	Fastqsanger.gz
	SRR15150474.fastq.gz	Fastqsanger.gz

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Similar Datasets

Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences

Project description:Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences

| PRJNA746964 | ENA

Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [ChIP-Seq]

Project description:Somatic hypermutation (SHM) drives the genetic diversity of immunoglobulin genes in activated B cells and supports the generation of antibodies with increased affinity for antigen. SHM is targeted to Ig genes by their enhancers (DIVACs; diversification activators) but how the enhancers mediate this activity is unknown. We show that DIVACs that strongly stimulate SHM increase the phosphorylation of RNA polymerase 2 (Pol2) and Pol2 occupancy in the mutating gene with little or no accompanying increase in elongation-competent Pol2 or production of full length transcripts, indicating the accumulation of stalled Pol2. DIVAC-induced stalling is weakly associated with an increase in the detection of single-stranded DNA bubbles in the mutating target gene. We did not find evidence for anti-sense transcription or an association of H3K27ac with DIVAC activity in the mutating gene. These findings argue for a connection between Pol2 stalling and cis-acting targeting elements in the context of SHM and thus define a mechanistic basis for locus-specific targeting of SHM in the genome. Our results suggest that DIVACs make the target gene a suitable platform for AID-mediated mutation without the need for increasing transcriptional output.

2021-10-22 | GSE180177 | GEO

Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [GRO-seq]

2021-10-22 | GSE180176 | GEO

Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [GRO-seq]

Project description:Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences [GRO-seq]

| PRJNA746967 | ENA

Immunoglobulin enhancers increase RNA polymerase 2 stalling at somatic hypermutation target sequences

Project description:This SuperSeries is composed of the SubSeries listed below.

2021-10-22 | GSE180178 | GEO

Ig Enhancers Increase RNA Polymerase II Stalling at Somatic Hypermutation Target Sequences.

Project description:Somatic hypermutation (SHM) drives the genetic diversity of Ig genes in activated B cells and supports the generation of Abs with increased affinity for Ag. SHM is targeted to Ig genes by their enhancers (diversification activators [DIVACs]), but how the enhancers mediate this activity is unknown. We show using chicken DT40 B cells that highly active DIVACs increase the phosphorylation of RNA polymerase II (Pol II) and Pol II occupancy in the mutating gene with little or no accompanying increase in elongation-competent Pol II or production of full-length transcripts, indicating accumulation of stalled Pol II. DIVAC has similar effect also in human Ramos Burkitt lymphoma cells. The DIVAC-induced stalling is weakly associated with an increase in the detection of ssDNA bubbles in the mutating target gene. We did not find evidence for antisense transcription, or that DIVAC functions by altering levels of H3K27ac or the histone variant H3.3 in the mutating gene. These findings argue for a connection between Pol II stalling and cis-acting targeting elements in the context of SHM and thus define a mechanistic basis for locus-specific targeting of SHM in the genome. Our results suggest that DIVAC elements render the target gene a suitable platform for AID-mediated mutation without a requirement for increasing transcriptional output.

| S-EPMC8702490 | biostudies-literature

Bach2 regulates AID-mediated immunoglobulin gene conversion and somatic hypermutation in DT40 B cells

Project description:The transcription factor Bach2 is required for germinal center formation and somatic hypermutation (SHM) of immunoglobulins, both central to an efficient antibody-mediated immune response. Activation-induced cytidine deaminase (AID) initiates SHM and CSR in germinal centers and has potential to induce human B cell lymphoma. To understand the role of Bach2 in AID-mediated immunoglobulin gene diversification processes, we established a Bach2-deficient DT40 B cell line. We show that in addition to allowing SHM, Bach2 drives immunoglobulin gene conversion (GCV), an important AID-dependent antibody gene diversification process. We demonstrate that Bach2 promotes GCV by increasing the expression of AID. Importantly, we found that the regulation of AID is independent of Blimp-1 and that Bach2-deficient cells have altered expression of several genes regulating AID expression, stability and function. These results demonstrate that Bach2 has a previously unappreciated role in the production of high-affinity antibodies.

2017-03-27 | GSE92430 | GEO

Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes

Project description:Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes

| PRJNA705367 | ENA

Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer-like sequences.

Project 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, NF?B, 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.

| S-EPMC3972084 | biostudies-literature

Role of Dot1L and H3K79 methylation in regulating somatic hypermutation of immunoglobulin genes

Project description:Somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) genes allow B cells to make antibodies that protect us against a wide variety of pathogens. SHM is mediated by activation induced deaminase (AID), occurs at a million times higher frequency than other mutations in the mammalian genome and is largely restricted to the variable (V) and switch (S) regions of Ig genes. Using the Ramos human Burkitt’s lymphoma cell line, we find that H3K79me2/3 and its methyltransferase Dot1L are more abundant on the V region than the constant (C) region which does not undergo mutation. In primary naïve mouse B cells examined ex vivo, the H3K79me2/3 modification appears constitutively in the donor Sμ and is inducible in the recipient Sγ1 upon CSR stimulation. Knockout (KO) and inhibition of Dot1L in Ramos cells significantly reduces V region mutation and the abundance of H3K79me2/3 on the V region and is associated with a decrease of Pol II and its S2 phosphorylated form at the IgH locus. KO of Dot1L also decreases the abundance of BRD4 and CDK9 (a subunit of P-TEFb complex) on the V region and this is accompanied by decreased nascent transcripts throughout the IgH gene. Treatment with JQ1 (inhibitor of BRD4) or DRB (inhibitor of CDK9) decreased SHM and the abundance of Pol II S2P at the IgH locus. With all these factors playing a role in transcription elongation, our studies extend our insights into the chromatin context and dynamics of transcription required for SHM.

2021-02-28 | GSE167873 | GEO

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