Ontology highlight
ABSTRACT:
PROVIDER: PRJNA830503 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18858100_1.fastq.gz | Fastqsanger.gz | |||
| SRR18858100_2.fastq.gz | Fastqsanger.gz | |||
| SRR18858101.fastq.gz | Fastqsanger.gz | |||
| SRR18858101_1.fastq.gz | Fastqsanger.gz | |||
| SRR18858101_2.fastq.gz | Fastqsanger.gz |
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Project description:SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B-cell lymphomagenesis
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Project description:SETD2 is the sole chromatin modifier responsible for H3K36me3, a histone mark linked to splicing, transcription initiation and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is virtually always heterozygous in diffuse large B-cell lymphomas (DLBCL). Here we show that heterozygous SETD2 deficiency results in germinal center (GC) hyperplasia and accelerated lymphomagenesis. SETD2 haploinsufficient GC B-cells exhibit increased competitive fitness and reduced DNA damage checkpoint activity, resulting in decreased apoptosis. SETD2 haploinsufficient GCB and lymphoma cells featured increased off- and on-target AICDA induced somatic hypermutation (SHM), complex structural variants such as rygma, and increased translocations including those activating MYC. DNA damage was selectively increased on the non-template strand and H3K36me3 loss was associated with greater RNA Pol II processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination during transcription. Hence, SETD2 haploinsufficiency delineates a novel GC B-cell context specific oncogenic pathway involving defective epigenetic surveillance of AICDA mediated somatic hypermutation induced off target effects on transcribed genes.
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Project description:Changes in DNA methylation are required for the formation of germinal centers (GC), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated recently in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCB) isolated from wild type (WT) and AID-deficient (Aicda-/-) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda-/- animals. Differentially methylated cytosines (DMCs) between GCB and naïve B cells (NB) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells. ERRBS and RNA-seq of wild type and Aicda knockout murine naive and germinal center B cells. ERRBS of human naive and germinal center B cells
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Project description:Productive B cell responses are critical to protect a host from infection. The spleen and lymph nodes are populated by resting follicular B cells, which can enter germinal centers upon antigen encounter. Once in the germinal center, B cells migrate between the dark and light zones, where they undergo somatic hypermutation and selection, respectively. While germinal center B cells have been studied, an intense molecular understanding of these cells/subsets (and the differences between them) is lacking.
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Project description:AICDA-induced epigenetic plasticity accelerates germinal center-derived lymphomagenesis
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Project description:Changes in DNA methylation are required for the formation of germinal centers (GC), but the mechanisms of such changes are poorly understood. Activation-induced cytidine deaminase (AID) has been recently implicated recently in DNA demethylation through its deaminase activity coupled with DNA repair. We investigated the epigenetic function of AID in vivo in germinal center B cells (GCB) isolated from wild type (WT) and AID-deficient (Aicda-/-) mice. We determined that the transit of B cells through the GC is associated with marked locus-specific loss of methylation and increased methylation diversity, both of which are lost in Aicda-/- animals. Differentially methylated cytosines (DMCs) between GCB and naïve B cells (NB) are enriched in genes that are targeted for somatic hypermutation (SHM) by AID and these genes form networks required for B cell development and proliferation. Finally, we observed significant conservation of AID-dependent epigenetic reprogramming between mouse and human B cells.
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