Similar Datasets
Project description:We aimed to understand the transcriptional impact of monoallelic loss of DOT1L in cortical nuclei from 10 week old mice.
2025-11-13 | GSE279120 | GEO
Project description:ChIP-seq analysis of control and DOT1L HET cortical nuclei.
| PRJNA1240293 | ENA
Project description:In order to understand the role of H3K79me2 and DOT1L during CNS development, we analysed neural stem cells after pharmacological inhibition of DOT1L (5 µM SGC0946). To identify target genes of DOT1L in the cortex, we determined the transcriptome of cortical progenitor cells derived from E14.5 NMRI mice after interference with DOT1L activity for three days in vitro (DIV3). Therefore, three independent experiments were performed (ctrl1 – inh1, ctrl2 – inh2, ctrl3 – inh3).
2015-12-31 | E-MTAB-3521 | biostudies-arrayexpress
Project description:Our group has reported that the histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered postmitotic differentiation/maturation.
2023-08-01 | GSE221994 | GEO
Project description:Osteoclasts are absorptive cells and play a critical role in homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic regulation of osteoclastogenesis. In this study, we investigated the role of DOT1L, which regulates gene expression epigenetically by histone H3K79 methylation during osteoclast formation. DOT1L and H3K79me2 levels were upregulated during osteoclast differentiation. Small molecule inhibitor- (EPZ5676 or EPZ004777) or short hairpin RNA-mediated reduction in DOT1L expression promoted osteoclast differentiation and resorption. DOT1L inhibition also increased osteoclast area and accelerated bone mass reduction in a mouse ovariectomy (OVX) model of osteoporosis. DOT1L inhibitors did not alter osteoblast differentiation in vitro and in vivo. Proteomics data, together with bioinformatics analysis, revealed that DOT1L inhibition altered reactive oxygen species (ROS) generation, autophagy activation, and cell fusion-related protein expression. ROS generation increased, and autophagy activation and cell migration ability enhancement were verified subsequently by flow cytometry and transwell migration assays. DOT1L inhibition increased NFATc1 nuclear translocation and NF-κB activation and strengthend osteoclast fusion and expression of resorption-related protein CD9, and MMP9 in osteoclasts derived from RAW264.7. Our findings support a new mechanism of DOT1L-mediated H3K79me2 epigenetic regulation of osteoclast differentiation, implicating DOT1L as a new therapeutic target for osteoclast dysregulation-induced disease.
2018-01-24 | PXD006448 | Pride
Project description:DOT1L is an epigenetic regulator that promotes gene expression by methylating lysine 79 on histone H3 and recruits transcription factors to gene targets. DOT1L is also an oncogenic driver in cancers that affect developing lymphocytes, yet how DOT1L activity regulates B-cell maturation remains poorly defined. Here, we use deep-sequencing and conditional knockout models to elucidate gene targets of H3K79me2, and the mechanistic contribution of DOT1L, during key stages of murine B-cell development. In the bone marrow, Dot1l was upregulated in pro B-cells. Deep-sequencing revealed that H3K79me2 accumulated during maturation. The genomic distribution of H3K79me2 peaks indicating that DOT1L regulates transcription and the cell cycle across different stages of B-cell development. As such, DOT1L was found to be essential for pre B-cell expansion, leading to a significant decrease in pre B-cells in the absence of DOT1L and a skewing of the B-cell receptor repertoire to favor proximal VH usage. In addition to the effective generation of a diverse B-cell pool, DOT1L was also required to establish the marginal zone (MZ) B-cell gene expression program. Attenuation of MZ B-cells and a bottlenecking at the pre-MZ B-cell stage in Dot1L-deficient mice correlated to H3K79me2 peaks at key MZ-regulatory genes such as Lfng and Dock10 in developing B cells. In contrast, Dot1l was re-expressed in germinal center (GC) B-cells post-immunization to deposit H3K79me2 at key GC B-cell gene loci during GC differentiation. Together, these data demonstrate a vital role for DOT1L during B cell lymphopoiesis, MZ B-cell generation and GC B-cell biology.
2025-09-01 | GSE306634 | GEO
Project description:Estrogen Receptor alpha (ERα) is a ligand-inducible transcription factor that mediates estrogen signaling in hormone-responsive breast cancer (BC) and is the primary target of specific anticancer therapies that although effective can generate resistance phenomena that represents a crucial problem in clinical management of patients affected by this disease. DOT1 Like Histone Lysine Methyltransferase (DOT1L) and Menin 1 (MEN1) have been identified as functional component of the ERα mechanism of action. To investigate the involvement of DOT1L and MEN1 in mediating ERα actions in hormone-responsive and endocrine-resistant BC, interaction proteomics was applied to map the DOT1l and MEN1 nuclear interacting partners in MCF7 breast cancer cell nuclei in order to the identifiy new possible therapeutic targets for a more effective pharmacological treatment of endocrine therapy-resistant tumors.
2022-08-12 | PXD026864 | Pride
Project description:Purpose: To characterize the genome-wide distribution of H3K79me2 in human leukemia cell lines treated with the Dot1l inhibitor EPZ004777 or control Methods: We performed Chip-seq for the H3K79me2 on the leukemia cell lines Mutz3, Loucy and Molm14 after 6 days in culture in the presence of 3uM EPZ004777 or DMSO control Results: H3K79me2 is completely erased from key target genes such as the HOXA cluster. Conclusions: Exposure of Mutz3, Loucy and Molm14 to 3uM EPZ004777 erases H3K79 methylation globally as well as on key loci ChIP-Seq for H3K79me2 on human leukemia cell lines exposed for 6 days to the Dot1l inhibitor EPZ004777
2016-01-12 | E-GEOD-76745 | biostudies-arrayexpress
Project description:We transduced two individual murine KMT2A-MLLT3 AML samples with DOT1L and three days after sorting for DOT1L+ cells collected for RNA-seq MLL-rearranged leukemias have been previously shown to be dependent on the presence of histone 3 lysine 79 (H3K79) dimethylation on the genomic targets of the fusion, and an inhibitor of the H3K79 methyltransferase DOT1L is in clinical trials for MLL-rearranged leukemia. In order to ask what biologic effects overexpression of DOT1L would have on the H3K79me2 ChIP-Seq profiles and MLL-fusion target gene expression, murine leukemias generated by transplanting MSCV-MLL-AF9-GFP transduced lin- cKit+ Sca1+ bone marrow cells were subjected to overexpression of DOT1L. Cells were sorted into low (low level of DOT1L overexpression), high (high level of DOT1L overexpression) and bulk (entire population) samples, and subjected to H3K79me2 ChIP-Seq (using a drosophila spike in for normalization) and RNA-Seq analysis 3 days after transduction.
2019-07-10 | GSE134035 | GEO