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DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ChIP-seq)

ABSTRACT: DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ChIP-seq)

PROVIDER: PRJNA483455 | ENA |

REPOSITORIES: ENA

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DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (RNA-seq)

Project description:DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (RNA-seq)

| PRJNA528308 | ENA

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ATAC-seq)

Project description:DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ATAC-seq)

| PRJNA483453 | ENA

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (Capture-C)

Project description:DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (Capture-C)

| PRJNA483454 | ENA

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ChIP-seq)

Project description:Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.

2019-05-30 | GSE117864 | GEO

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (Capture-C)

2019-05-30 | GSE117863 | GEO

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (ATAC-seq)

2019-05-30 | GSE117862 | GEO

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation (RNA-seq)

2019-05-30 | GSE128632 | GEO

DOT1L inhibition reveals a distinct subset of enhancers dependent on H3K79 methylation.

Project description:Enhancer elements are a key regulatory feature of many important genes. Several general features including the presence of specific histone modifications are used to demarcate potentially active enhancers. Here we reveal that putative enhancers marked with H3 lysine 79 (H3K79) di or trimethylation (me2/3) (which we name H3K79me2/3 enhancer elements or KEEs) can be found in multiple cell types. Mixed lineage leukemia gene (MLL) rearrangements (MLL-r) such as MLL-AF4 are a major cause of incurable acute lymphoblastic leukemias (ALL). Using the DOT1L inhibitor EPZ-5676 in MLL-AF4 leukemia cells, we show that H3K79me2/3 is required for maintaining chromatin accessibility, histone acetylation and transcription factor binding specifically at KEEs but not non-KEE enhancers. We go on to show that H3K79me2/3 is essential for maintaining enhancer-promoter interactions at a subset of KEEs. Together, these data implicate H3K79me2/3 as having a functional role at a subset of active enhancers in MLL-AF4 leukemia cells.

| S-EPMC6594956 | biostudies-literature

DOT1L inhibition reveals a distinct class of enhancers dependent upon H3K79 methylation

Project description:DOT1L inhibition reveals a distinct class of enhancers dependent upon H3K79 methylation

| PRJNA483451 | ENA

DOT1L-controlled cell-fate determination and transcription elongation are independent of H3K79 methylation

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

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