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DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE233975 | GEO | 2025/11/13

REPOSITORIES: GEO

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DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [ChIP-seq]

Project description:Activation-induced deaminase (AID) initiates class switch recombination (CSR) and somatic hypermutation of immunoglobulin genes, which are required for efficient antibody responses. Collaterally, AID can also mutate a set of off-target genes with oncogenic consequences. The mechanisms that make such loci susceptible to AID are not fully understood. We find that the H3K79 histone methyltransferase DOT1L is located close to AID in the nucleus. Not only does DOT1L activity facilitate CSR, but it also facilitates AID off-target activity, including Igh-cMyc translocations. Genes mutated by AID display high DOT1L activity. DOT1L deficiency causes mostly increased nascent transcription, accompanied by a modest reduction in RNAPII occupancy. By integrating different genomic approaches, we discovered that DOT1L restricts the velocity of transcription elongation proportionally to the level of higher order H3K79 methylation (H3K79me2/3) and favors RNAPII pausing. These transcriptional conditions enhance AID occupancy and, consequently, its activity. Our data indicate a role for DOT1L and H3K79me2/3 in limiting transcription and highlight stronger RNAPII pausing and attenuated RNAPII elongation velocity as critical steps for productive AID association and mutagenesis at target loci. Furthermore, increased transcription elongation velocity could explain both upregulation and downregulation of genes in DOT1L-deficient cells.

2025-11-13 | GSE290944 | GEO

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [CUT&RUN]

2025-11-13 | GSE233969 | GEO

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [RNA-Seq]

2025-11-13 | GSE233974 | GEO

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [TT(chem)-seq]

2025-11-13 | GSE290945 | GEO

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID

Project description:DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID

| PRJNA979129 | ENA

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [ChIP-seq]

Project description:DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [ChIP-seq]

| PRJNA1231055 | ENA

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [CUT&RUN]

Project description:DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [CUT&RUN]

| PRJNA979133 | ENA

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [RNA-Seq]

Project description:DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [RNA-Seq]

| PRJNA979137 | ENA

DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [TT(chem)-seq]

Project description:DOT1L activity limits transcription elongation velocity and favors RNAPII pausing to facilitate mutagenesis by AID. [TT(chem)-seq]

| PRJNA1231056 | ENA

Slow RNAPII Transcription Elongation Rate, Low Levels of RNAPII Pausing, and Elevated Histone H1 Content at Promoters Associate with Higher m6A Deposition on Nascent mRNAs.

Project description:N6-methyladenosine modification (m6A) fine-tunes RNA fate in a variety of ways, thus regulating multiple fundamental biological processes. m6A writers bind to chromatin and interact with RNA polymerase II (RNAPII) during transcription. To evaluate how the dynamics of the transcription process impact m6A deposition, we studied RNAPII elongation rates in mouse embryonic stem cells with altered chromatin configurations, due to reductions in linker histone H1 content. We found that genes transcribed at slow speed are preferentially methylated and display unique signatures at their promoter region, namely high levels of histone H1, together with marks of bivalent chromatin and low RNAPII pausing. They are also highly susceptible to m6A loss upon histone H1 reduction. These results indicate that RNAPII velocity links chromatin structure and the deposition of m6A, highlighting the intricate relationship between different regulatory layers on nascent mRNA molecules.

| S-EPMC9498810 | biostudies-literature

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