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Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [TT-seq]

ABSTRACT: Activation-induced deaminase (AID) drives antibody diversification through class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes, but its mutagenic activity at several hundred other genes and enhancers contributes to B cell lymphoma. Despite its physiological and pathological relevance, how AID selectively mutates the Ig and a restricted set of off-target genes is unknown. Transcription is required for AID activity, but most transcribed genes are not mutated, and AID occupies more loci than it mutates. Here, we identify the Super Elongation Complex (SEC) histone readers MLLT1 and MLLT3 as determinants of selective AID activity. Combined loss of MLLT1 and MLLT3 abolishes all AID-dependent processes, phenocopying AID deficiency. AID-mutated genomic regions are precisely marked by high MLLT1 and MLLT3 occupancy (MLLT1/3high) in mouse and human B cells, while nascent transcription remains largely unchanged in MLLT1- or MLLT3-deficient cells, indicating a direct role in licensing AID activity. Mechanistically, MLLT1 and MLLT3 are dispensable for global AID chromatin tethering but link AID to transcription elongation. In mice, both readers bind AID and are partially redundant, but MLLT1 plays a dominant role through its intrinsically disordered region, which promotes condensate formation and selectively concentrates AID. Fusing AID to MLLT1 or MLLT3 is sufficient to restore CSR and mutagenesis in SEC-deficient cells. These findings reveal how MLLT1/3high licenses AID at a restricted subset of genomic regions by spatially confining and concentrating its activity, likely through condensate-based mechanisms.

ORGANISM(S): Mus musculus

PROVIDER: GSE336464 | GEO | 2026/08/17

REPOSITORIES: GEO

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Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [ChIP-seq]

Project description:Activation-induced deaminase (AID) drives antibody diversification through class switch recombination (CSR) and somatic hypermutation (SHM) of immunoglobulin (Ig) genes, but its mutagenic activity at several hundred other genes and enhancers contributes to B cell lymphoma. Despite its physiological and pathological relevance, how AID selectively mutates the Ig and a restricted set of off-target genes is unknown. Transcription is required for AID activity, but most transcribed genes are not mutated, and AID occupies more loci than it mutates. Here, we identify the Super Elongation Complex (SEC) histone readers MLLT1 and MLLT3 as determinants of selective AID activity. Combined loss of MLLT1 and MLLT3 abolishes all AID-dependent processes, phenocopying AID deficiency. AID-mutated genomic regions are precisely marked by high MLLT1 and MLLT3 occupancy (MLLT1/3high) in mouse and human B cells, while nascent transcription remains largely unchanged in MLLT1- or MLLT3-deficient cells, indicating a direct role in licensing AID activity. Mechanistically, MLLT1 and MLLT3 are dispensable for global AID chromatin tethering but link AID to transcription elongation. In mice, both readers bind AID and are partially redundant, but MLLT1 plays a dominant role through its intrinsically disordered region, which promotes condensate formation and selectively concentrates AID. Fusing AID to MLLT1 or MLLT3 is sufficient to restore CSR and mutagenesis in SEC-deficient cells. These findings reveal how MLLT1/3high licenses AID at a restricted subset of genomic regions by spatially confining and concentrating its activity, likely through condensate-based mechanisms.

2026-08-17 | GSE336330 | GEO

Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity

Project description:Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity

| PRJNA1481663 | ENA

Project description:Histone readers MLLT1 and MLLT3 concentrate AID to confer locus specificity

| PRJNA1481264 | ENA

Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [ChIP-seq]

Project description:Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [ChIP-seq]

| PRJNA1481260 | ENA

Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [TT-seq]

Project description:Concentration by histone readers MLLT1 and MLLT3 confers locus specificity to AID activity [TT-seq]

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DOT1L enables Activation Induced Deaminase activity genome-wide by limiting RNAPII promoter proximal pause release

Project description:Activation induced deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation of the antibody genes but also mutates other genes, with oncogenic consequences, as a side effect. It is important to understand the mechanisms that render the antibody genes and off-target genomic loci susceptible to AID. We identify the H3K79 histone methyltransferase DOT1L as nuclear AID-proximal factor required for CSR, as well as off-target AID activity, including IgH-cMyc translocations. Mechanistically, we find that DOT1L activity restricts transcriptional pause release, as evidenced by reduced promoter-proximal RNA polymerase II (RNAPII) and increased RNAPII Serine 2 phosphorylation into the gene bodies of all H3K79-modified genes. Additional evidence suggests that widespread pause release results in abnormal transcription elongation, which can explain the variable effect of DOT1L-deficiency on H3K79-methylated gene transcript levels, depending on their original transcriptional activity and gene length. Thus, we propose that DOT1L limits transcriptional pause release, which enables AID activity genome-wide.

2023-05-31 | MSV000092065 | MassIVE

Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig loci in activated B cells

Project description:After immunization or infection, activation-induced cytidine deaminase (AID) initiates diversification of immunoglobulin (Ig) genes in B cells, introducing mutations within the antigen binding V regions (somatic hypermutation, SHM) and double-strand DNA breaks (DSBs) into switch (S) regions, leading to antibody class switch recombination (CSR). Using a candidate approach, AID has been shown to initiate mutations at numerous non-Ig genes in B cells in Peyer’s patches. However, it is not known if during B cell activation, AID also induces DNA breaks at genes other than IgH genes, which would lead to genomic instability and malignancy. Using a non-biased genome-wide approach, we have identified hundreds of reproducible AID-dependent DSBs in mouse splenic B cells shortly after induction of CSR in culture. Most interestingly, AID induces DSBs at sites syntenic with sites of translocations, deletions, and amplifications found in human B cell lymphomas, including within the oncogene B cell lymphoma11a (bcl11a)/evi9. The AID-dependent DSBs are not restricted to transcribed regions, and they frequently occur within repeated sequence elements, including CA and non-CA repeats, and SINEs. Comparison of Nbs1 binding sites in wild-type vs. aid-/- splenic B cells induced to undergo CSR; aid-dependent Nbs1 sites correlated with gene transcription (RNA Pol2).

2011-01-21 | E-GEOD-24827 | biostudies-arrayexpress

A broad atlas of somatic hypermutation allows prediction of activation-induced deaminase targets.

Project description:Activation Induced Deaminase (AID) initiates somatic hypermutation (SHM) and class switch recombination (CSR) in germinal center (GC) B cells through the deamination of deoxycytidine residues (dC) into deoxyuridines (dU) in immunoglobulin (Ig) genes. Although AID has a strong preference for Ig genes, it can also target other genomic regions, giving rise to mutations or chromosomal translocations. Thus, understanding the specificity of AID has major implications for oncogenic transformation. However, approaching AID specificity has proved extremely challenging because AID deamination events occur at low frequencies. Here we have sequenced at very high depth >1500 genomic regions from GC B cells and identified 275 genes targeted by AID, including 30 of the previously known 35 AID targets. This has enabled for the first time to define the molecular features predictive of AID target specificity genome-wide. Furthermore, we identify the most highly mutated hotspot for AID activity described to date. We also find that Base Excision Repair (BER) and Mismatch Repair (MMR) systems, which are responsible for the resolution of AID deaminations, back-up each other to faithfully repair AID-induced lesions. Finally, our data establishes a novel link between AID mutagenic activity and malignant transformation.

2018-01-19 | GSE102944 | GEO

Activation-induced cytidine deaminase induces reproducible DNA breaks at many non-Ig loci in activated B cells

2011-01-21 | GSE24827 | GEO

RNA-sequencing of Nedd4+/+ and Nedd4-/- mouse splenic B cells

Project description:Programmed mutagenesis of the immunoglobulin locus of B-lymphocytes during class switch recombination and somatic hypermutation requires RNA polymerase II (RNA polII) transcription complex dependent targeting of the DNA mutator, Activation Induced cytidine Deaminase (AID). AID deaminates cytidine residues on substrate sequences in the immunoglobulin (Ig) locus via a transcription-dependent mechanism and this activity is stimulated by the RNA polII stalling co-factor Spt5 and the eleven-subunit cellular non-coding RNA 3’-5’ exonucleolytic processing complex, RNA exosome. The mechanism by which the RNA exosome recognizes immunoglobulin locus RNA substrates to stimulate AID DNA deamination activity on its in vivo substrate sequences is an important question. Here we report that E3-ubiquitin ligase Nedd4 destabilizes AID-associated RNA polII by a ubiquitination event leading to generation of 3’-end free RNA exosome RNA substrates at the Ig locus and other AID target sequences genome-wide. Using highthrough-out RNA sequencing technology, we find that lack of Nedd4 activity in B cells leads to accumulation of RNA exosome substrates at AID target genes. Moreover, we find that Nedd4-deficient B cells are inefficient in undergoing class switch recombination. Taken together, our study links non-coding RNA processing following RNA polymerase II pausing with regulation of the mutator AID protein. Our study also identifies Nedd4 as a regulator of non-coding RNA that are generated by stalled RNA polII genome-wide. Splenic B cells from Nedd4+/+ and Nedd4-/- B cells fetal liver chimeric mice were were stimulated in culture for IgG1 CSR. Total RNA was isolated and evaluated with whole genome RNA-seq

2013-08-07 | E-GEOD-49027 | biostudies-arrayexpress

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