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DOT1L-mediated Murine Neuronal Differentiation associates with H3K79me2 Accumulation and preserves SOX2-Enhancer Accessibility

ABSTRACT: DOT1L-mediated Murine Neuronal Differentiation associates with H3K79me2 Accumulation and preserves SOX2-Enhancer Accessibility

PROVIDER: PRJNA558383 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11878619_1.fastq.gz	Fastqsanger.gz
	SRR11878619_2.fastq.gz	Fastqsanger.gz
	SRR11878620_1.fastq.gz	Fastqsanger.gz
	SRR11878620_2.fastq.gz	Fastqsanger.gz
	SRR11878621_1.fastq.gz	Fastqsanger.gz

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DOT1L-mediated Murine Neuronal Differentiation associates with H3K79me2 Accumulation and preserves SOX2-Enhancer Accessibility

Project description:To study whether acute inhibition of DOT1L induces global chromatin states alterations, we profile and compare the transcriptome, chromatin accessibility and epigenome (H3K4me3, H3K4me1, H3K27ac, H3K27me3, H3K36me3, H3K9me3, H3K79me2) of mESC and ES-derived NPC, treated with DMSO or EPZ5676.

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DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility.

Project description:During neuronal differentiation, the transcriptional profile and the epigenetic context of neural committed cells is subject to significant rearrangements, but a systematic quantification of global histone modification changes is still missing. Here, we show that H3K79me2 increases and H3K27ac decreases globally during in-vitro neuronal differentiation of murine embryonic stem cells. DOT1L mediates all three degrees of methylation of H3K79 and its enzymatic activity is critical to modulate cellular differentiation and reprogramming. In this context, we find that inhibition of DOT1L in neural progenitor cells biases the transcriptional state towards neuronal differentiation, resulting in transcriptional upregulation of genes marked with H3K27me3 on the promoter region. We further show that DOT1L inhibition affects accessibility of SOX2-bound enhancers and impairs SOX2 binding in neural progenitors. Our work provides evidence that DOT1L activity gates differentiation of progenitors by allowing SOX2-dependent transcription of stemness programs.

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DOT1L-mediated H3K79me2 directs B-cell repertoire establishment, marginal zone development and germinal center function

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.

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H3K79me2 naïve and in vitro activated B cells

Project description:We studied the role of the histone methyltransferase DOT1L in B cell development and differentiation. H3K79me2 ChIP-sequencing data was generated from sorted B cells. This was compared to RNA-sequencing data from WT and Dot1L KO mice in order to study the link between H3K79me2 and transcription.

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Assesment of DOT1L direct targets via ChIP of H3K79me2 at E12.5 of mouse cortex

Project description:Cortical development is under control of transcriptional programs that are orchestrated by activation of key determinants such as transcription factors. But stable inheritance of temporo-spatial activity of factors influencing cell fate and regionalization in different layers is only partly understood. We report that chromatin methylation at H3K79 transmits cell fate and layering information from early to late progenitors. Activity of DOT1L, mediating H3K79 methylation, prevents premature cell cycle exit by increasing expression of genes regulating asymmetric cell division (Vangl2, Cenpj). Transcriptional programs characteristic for upper layer neurons are less active in Dot1l-deficient mice already at developmental stages that precede upper layer neuron generation. DOT1L activates expression of many key determinants such as Cux1, Cux2, Satb2 or Pou3f3. Additionally, DOT1L affects transcription of Sox family members, suggesting an evolutionary conserved mechanism. In part, DOT1L and H3K79me2 replace inactivating H3K9me3 at Sox family promoters and allow for transcriptional activation during neural differentiation.

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Expression profiling of WT and Dot1L KO CD8 effector T cells and H3K79me2 occupancy in WT effector CD8 T cells

Project description:We studied the role of the histone methyltransferase DOT1L in T cell development and differentiation. We generated RNA-seq data from sorted CD8 effector T cells from WT (Lck-cre+/-) and Dot1L KO (Lck-cre+/-;Dot1Lfl/fl) mice infected with Listeria monocytogenes. This data was compared with H3K79me2 ChIP-seq data from the same T cell subset.

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H3K79me2 and H3K4me3 in CD8 T cell subsets

Project description:We studied the role of the histone methyltransferase DOT1L in T cell development and differentiation. H3K79me2 and H3K4me3 ChIP-sequencing data was generated from sorted CD8 single positive thymocytes, naïve CD8 splenocytes and memory CD8 splenocytes. This was compared to RNA-sequencing data from WT and Dot1L KO mice in order to study the link between H3K79me2 and transcription.

2020-07-29 | GSE138908 | GEO

Nucleophosmin 1 regulates H3K79me2 levels and peri-nucleolar heterochromatin organization through interaction with the methyltransferase DOT1L [ChIP-seq]

Project description:The histone methyltransferase DOT1L catalyzes methylation of H3K79 and it is highly conserved in mammals. DOT1L plays a functional role in several biological processes including cell cycle regulation, DNA repair, RNA splicing and gene expression, suggesting a complex role in chromatin organization and regulation. Such a remarkable range of functions performed by DOT1l can be the result, at least partially, of its interaction with different proteins and presence in different complexes. Here, we characterized the interaction of DOT1L with the nucleolar protein NPM1 and the impact of the DOT1L/NPM1 complex on nucleoli organization and activity. We show that i) DOT1L interacts preferentially with monomeric NPM1 in the nucleus; ii) DOT1L interaction with NPM1 is key to maintain their protein homeostasis; iii) NPM1 depletion results in H3K79me2 upregulation at chromatin remodeling genes; iv) DOT1L/NPM1 complex preserved peri-nucleolar heterochromatin organization via epigenetic mechanisms. Our findings unravel the molecular mechanisms employed by the DOT1L/NPM1 complex to maintain heterochromatin organization around the nucleoli and shed light on one aspect of the complex role of DOT1L in chromatin dynamics.

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H3K79me2 ChIP-seq analysis of murine AML with DOT1L overexpressed

Project description:H3K79me2 ChIP-seq analysis of murine AML with DOT1L overexpressed

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Inhibition of DOT1L increases osteoclast fusion and resorption and aggravates bone loss

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

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