Similar Datasets
Project description:Proper functioning of the lymphatic system is required for normal immune response, fluid balance and lipid reabsorption. Multiple regulatory mechanisms are employed to ensure correct formation of lymphatic vessels; however, whether epigenetic regulation is involved in this process remains largely unknown. We report that epigenetic priming by the Disruptor of telomeric silencing 1-like (DOT1L) in endothelial cell (EC) is indispensable for generation and function of lymphatic endothelial cells (LECs). Loss function of DOT1L leads to reduction of H3K79 di-methylation and expression of the genes important for LEC development and function. Thus, our study establishes DOT1L-mediated transcriptional regulation in ECs plays an important role in differentiation and function of LECs.
2018-10-10 | GSE104809 | GEO
Project description:Proper functioning of the lymphatic system is required for normal immune response, fluid balance and lipid reabsorption. Multiple regulatory mechanisms are employed to ensure correct formation of lymphatic vessels; however, whether epigenetic regulation is involved in this process remains largely unknown. We report that epigenetic priming by the Disruptor of telomeric silencing 1-like (DOT1L) in endothelial cell (EC) is indispensable for generation and function of lymphatic endothelial cells (LECs). Mechanistically, loss function of DOT1L leads to reduction of H3K79 di-methylation and expression of the genes important for LEC development and function. Thus, our study establishes DOT1L-mediated transcriptional regulation in ECs plays an important role in differentiation and function of LECs.
2018-10-10 | GSE104810 | GEO
Project description:Aberrant H3K79 dimethylation by DOT1L is a defining feature of MLL-rearranged (MLLr) acute myeloid leukemia (AML), but whether this modification influences alternative splicing remains unclear. Here, we performed H3K79me2 ChIP-seq and RNA-seq on primary samples from 24 MLLr AML patients, 4 wild-type MLL AML patients, and 4 healthy bone marrow donors. We found that a subset of exon skipping (SE) events was enriched at H3K79me2-occupied loci in MLLr samples. DOT1L inhibition with EPZ5676 led to broad changes in SE patterns, and many switched events showed concurrent reduction in local H3K79me2 signal. Pathway analysis of genes harboring these events revealed enrichment for RNA processing and splicing-related functions, with additional involvement of DNA repair and apoptosis-associated pathways. To identify potential mediators, we performed rapid immunoprecipitation mass spectrometry (RIME) in MV4-11 and MOLM-14 cells and detected SRSF2 and hnRNP family proteins in complex with DOT1L; these interactions were confirmed by co-immunoprecipitation. Combined inhibition of DOT1L and selected splicing factors reduced cell proliferation more effectively than single-agent treatment, both in MLLr cell lines and in xenograft models. These results indicate that H3K79me2 contributes to alternative splicing regulation through splicing factor recruitment in MLLr AML and provide a rationale for coordinated epigenetic–splicing therapeutic strategies.
2026-02-26 | GSE320036 | GEO
Project description:DOT1L as methyltransferase of H3K79 is implicated in brian development. Here, we further defined DOT1L function within the granular neurons during cerebellar development using ChIP-seq of H3K79 dimethylation of isolated cerebellar granular neurons and progenitors. Thereby we compared samples treated with a DOT1L inhibitor versus DMSO treated cells. The data sets reveals new important targets of DOT1L, which ensure a correct development of the cerebellum.
2018-10-15 | GSE101947 | GEO
Project description:We report the application of ChIP sequencing technology for high-throughput profiling of H3K79me2 in prostate cancer cells. We generated genome-wide maps of LNCaP and PC3 cells that were treated with the specific DOT1L inhibitor EPZ004777. We find that lysine 79 dimethylation is sensitive to DOT1L inhibition in both cell lines, however the enrichment of K79 methylated peaks differed between the two cell lines.
2019-08-09 | GSE135574 | GEO
Project description:Melanoma is a common and aggressive cancer, with a rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for some late-stage patients. Despite these advances, incomplete knowledge of genes and pathways that are gained or lost during melanogenesis prohibits cures for many patients. To identify gain of function and loss of function drivers of melanoma, we established a multi-omics cohort of melanoma patient-derived xenografts (melPDomiX). By linking mutations with gene and protein expression, we characterize gain or loss of function of specific melanoma drivers in treatment refractory tumor models. We use multi-omics integration and structural-context representation to distinguish gain from loss of function variants, revealing new candidate melanoma genes and targets. This study provides a comprehensive resource of tumor models with the genetic, molecular and structural features of gain and loss of function melanoma drivers, allowing future development of better therapeutics for this devastating and heterogenous malignancy.
2026-05-17 | GSE298502 | GEO
Project description:Chromosome 3p monosomy is associated with a poor clinical outcome of patients with uveal melanoma. Since a copy of the tumor suppressor miR-16 gene is lost for these patients, we postulated that a 3p loss may reduce the miR-16 amount and activity, promoting RNA derepression and tumor burden (loss of brake effect) as observed in chronic lymphocytic leukemia. Unexpectedly, we found that miR-16 expression level is not decreased despite the 3p monosomy. In contrast, our results suggested that miR-16 activity is impaired in uveal melanoma. Here, we investigated the molecular mechanism explaining the sequestration of miR-16 by RNAs. By defining the miR-16 interactome, two genes sets have been highlighted, suggesting two divergent miR-16 functions. In addition to the canonical miR-16 targets such as CCND3 and CDC25A, we identified another set of miR-16-interacting RNAs called thereafter miR-16 sponges. miR-16 binds to these RNAs sponge without inducing their decay. Mechanistically, the miR-16/RNA non-canonical base-pairing promoted stability of mRNAs involved in cancer cell proliferation. The biological relevance has been challenged in uveal melanoma. We showed that patients with poor overall survival expressed higher levels of miR-16 sponges and canonical miR-16 targets. These results strongly suggested that miR-16 is no longer able to repress its targets and, in contrast, promotes RNA stability and protein expression of oncogenes. miR-16 activity assessment using our Sponge-signature discriminates the patient’s overall survival as efficiently as the current method based on copy number variations and driver mutations detection. To conclude, miRNA loss of function due to miRNA sequestration seems to promote cancer burden by two combined events – 'loss of brake and an acceleration'. Our results highlight the oncogenic role of the non-canonical base-pairing between miRNAs/mRNAs in uveal melanoma.
2022-10-04 | E-MTAB-10940 | biostudies-arrayexpress
Project description:Melanoma is a common and aggressive cancer, with a rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for some late-stage patients. Despite these advances, incomplete knowledge of genes and pathways that are gained or lost during melanogenesis prohibits cures for many patients. To identify gain of function and loss of function drivers of melanoma, we established a multi-omics cohort of melanoma patient-derived xenografts (melPDomiX). By linking mutations with gene and protein expression, we characterize gain or loss of function of specific melanoma drivers in treatment refractory tumor models. We use multi-omics integration and structural-context representation to distinguish gain from loss of function variants, revealing new candidate melanoma genes and targets. This study provides a comprehensive resource of tumor models with the genetic, molecular and structural features of gain and loss of function melanoma drivers, allowing future development of better therapeutics for this devastating and heterogenous malignancy.
2026-05-17 | GSE297200 | GEO
Project description:We transduced two individual murine KMT2A-MLLT3 AML samples with DOT1L and three days after sorting for DOT1L+ cells were collected for ChIP-Seq. Before beginning the ChIP protocol drosophila melanogaster (S2) cells were spiked in at a 1:2 ratio.
2019-07-10 | GSE134030 | GEO
Project description:Melanoma is a common and aggressive cancer, with a rising incidence in most developed countries. Major discoveries in melanoma biology have been rapidly translated, allowing cures for some late-stage patients. Despite these advances, incomplete knowledge of genes and pathways that are gained or lost during melanogenesis prohibits cures for many patients. To identify gain of function and loss of function drivers of melanoma, we established a multi-omics cohort of melanoma patient-derived xenografts (melPDomiX). By linking mutations with gene and protein expression, we characterize gain or loss of function of specific melanoma drivers in treatment refractory tumor models. We use multi-omics integration and structural-context representation to distinguish gain from loss of function variants, revealing new candidate melanoma genes and targets. This study provides a comprehensive resource of tumor models with the genetic, molecular and structural features of gain and loss of function melanoma drivers, allowing future development of better therapeutics for this devastating and heterogenous malignancy.
2026-05-17 | GSE297199 | GEO