DOT1L-controlled cell-fate determination and transcription elongation are independent of H3K79 methylation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA553753 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9667090.fastq.gz | Fastqsanger.gz | |||
| SRR9667100.fastq.gz | Fastqsanger.gz | |||
| SRR9667110.fastq.gz | Fastqsanger.gz | |||
| SRR9667120.fastq.gz | Fastqsanger.gz | |||
| SRR9667130.fastq.gz | Fastqsanger.gz |
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Project description:Actively transcribed genes in mammals are decorated by H3K79 methylation, which is correlated with transcription levels and is catalyzed by the histone methyltransferase DOT1L. DOT1L is required for mammalian development, and the inhibition of its catalytic activity has been extensively studied for cancer therapy; however, the mechanisms underlying DOT1L’s functions in normal development and cancer pathogenesis remain elusive. To dissect the relationship between H3K79 methylation, cellular differentiation, and transcription regulation, we systematically examined the role of DOT1L and its catalytic activity in embryonic stem cells (ESCs). DOT1L is dispensable for ESC self-renewal but is required for establishing the proper expression signature of neural progenitor cells, while catalytic inactivation of DOT1L has a lesser effect. Furthermore, DOT1L loss, rather than its catalytic inactivation, causes defects in glial cell specification. Although DOT1L loss by itself has no major defect in transcription elongation, transcription elongation defects seen with the super elongation complex inhibitor KL-2 are exacerbated in DOT1L knockout cells, but not in catalytically dead DOT1L cells, revealing a role of DOT1L in promoting productive transcription elongation that is independent of H3K79 methylation. Taken together, our study reveals a catalytic-independent role of DOT1L in modulating cell-fate determination and in transcriptional elongation control.
2020-10-21 | GSE134083 | GEO
Project description:Actively transcribed genes in mammals are decorated by H3K79 methylation, which is correlated with transcription levels and is catalyzed by the histone methyltransferase DOT1L. DOT1L is required for mammalian development, and the inhibition of its catalytic activity has been extensively studied for cancer therapy; however, the mechanisms underlying DOT1L's functions in normal development and cancer pathogenesis remain elusive. To dissect the relationship between H3K79 methylation, cellular differentiation, and transcription regulation, we systematically examined the role of DOT1L and its catalytic activity in embryonic stem cells (ESCs). DOT1L is dispensable for ESC self-renewal but is required for establishing the proper expression signature of neural progenitor cells, while catalytic inactivation of DOT1L has a lesser effect. Furthermore, DOT1L loss, rather than its catalytic inactivation, causes defects in glial cell specification. Although DOT1L loss by itself has no major defect in transcription elongation, transcription elongation defects seen with the super elongation complex inhibitor KL-2 are exacerbated in DOT1L knockout cells, but not in catalytically dead DOT1L cells, revealing a role of DOT1L in promoting productive transcription elongation that is independent of H3K79 methylation. Taken together, our study reveals a catalytic-independent role of DOT1L in modulating cell-fate determination and in transcriptional elongation control.
| S-EPMC7959542 | biostudies-literature
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 | GSE233974 | GEO
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 | GSE233969 | GEO
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
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 | GSE290945 | GEO
Project description:The recognition of modified histones by “reader” proteins constitutes a key mechanism regulating gene expression in the chromatin context. Compared with the great variety of readers for histone methylation, few protein modules that recognize histone acetylation are known. Here we show that the evolutionarily conserved YEATS domains constitute a novel family of acetyllysine readers. The human AF9 YEATS domain binds strongly to histone H3K9 acetylation and, to a lesser extent, H3K27 and H3K18 acetylation. Crystal structural studies revealed that AF9 YEATS adopts an eight-stranded immunoglobin fold and utilizes a serine-lined aromatic “sandwiching” cage for acetyllysine readout, representing a novel recognition mechanism that is distinct from that of known acetyllysine readers. Histone acetylation recognition by AF9 is important for the chromatin recruitment of the H3K79 methyltransferase DOT1L. Together, our studies identify the YEATS domain as a novel acetyllysine-binding module, thereby establishing the first direct link between histone acetylation and DOTL1-mediated H3K79 methylation in transcription control. ChIP-seq analysis of AF9, H3K79me3, H3K9ac in Hela cells and H3K79me3 in Hela AF9 knockdown and Hela Dot1L knockdown cells.
2014-12-11 | E-GEOD-60366 | biostudies-arrayexpress
Project description:We wanted to investigate the effects of Dot1l deletion on gene expression in LSKs and GMPs of C57/BL6 mice Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes. Lineage negative Sca-1 positive Kit positive (LSK) cells and granulocyte macrophage progenitors (GMPs) were sorted from Dot1 wt/wt x Mx-Cre mice or Dot1l fl/fl x Mx-Cre mice were injected with PIPC. PIPC injection induced biallelic deletion of the Dot1l allele in the Dot1l fl/fl mice but not the Dot1l wt/wt mice. The Dot1l wt/wt LSKs and GMPs were compared to the Dot1l -/- counterparts by RNA extraction and Microarrays.
2014-09-08 | E-GEOD-54498 | biostudies-arrayexpress
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
Project description:We wanted to investigate the effects of Dot1l deletion on gene expression in LSKs and GMPs of C57/BL6 mice Aberrant Hox gene activation is a recurrent feature in several different types of human leukemia, including leukemias with rearrangements of the mixed lineage leukemia (MLL) gene. In this study, we demonstrate that Hox gene expression is controlled by higher degree H3K79 methylation in acute myeloid leukemia (AML). We show that the deposition of progressive H3K79 methylation states at the genomic loci of critical Hox genes is dependent on the interaction of the H3K79 methyltransferase Dot1l with Af10, a protein that is found in the Dot1l complex isolated from diverse cell types. Furthermore, abrogation of the Dot1l-Af10 interaction reverses aberrant epigenetic profiles found in the leukemia epigenome and impairs the transforming ability of mechanistically distinct AML oncogenes.
2014-09-08 | GSE54498 | GEO