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Genome-wide maps of chromatin histone methylation marks in neonatal and adult cardiomyocytes

ABSTRACT: Epigenetic changes in DNA and chromatin are implicated in organogenesis and cell differentiation. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach (ChIP-seq) we analyses the enrichment of H3K79me2 and H3K4me3 (histone methylation marks associated with transcriptional activation) and H3K27me3 and H3K9me3 (histone methylation marks associated with transcriptional repression) in neonatal and adult cardiomyocytes. The histone methylation profile obtained was correlated with an Illumina gene expression profile from the same samples. Our results demonstrate that histone methylation, and in particular the DOT1L-mediated H3K79me2 mark, drives cardiomyogenesis through the definition of a specific transcriptional landscape

ORGANISM(S): Mus musculus

PROVIDER: GSE45174 | GEO | 2014/12/22

SECONDARY ACCESSION(S): PRJNA193107

REPOSITORIES: GEO

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Genome-wide maps of chromatin histone methylation marks in neonatal and adult cardiomyocytes

Project description:Epigenetic changes in DNA and chromatin are implicated in organogenesis and cell differentiation. Through a genome-wide chromatin-immunoprecipitation DNA-sequencing approach (ChIP-seq) we analyses the enrichment of H3K79me2 and H3K4me3 (histone methylation marks associated with transcriptional activation) and H3K27me3 and H3K9me3 (histone methylation marks associated with transcriptional repression) in neonatal and adult cardiomyocytes. The histone methylation profile obtained was correlated with an Illumina gene expression profile from the same samples. Our results demonstrate that histone methylation, and in particular the DOT1L-mediated H3K79me2 mark, drives cardiomyogenesis through the definition of a specific transcriptional landscape Profiling of H3K79me2, H3K4me3, H3K27me3 and H3K9me3 in neonatal and adult cardiomyocytes

2014-12-22 | E-GEOD-45174 | biostudies-arrayexpress

Chromatin proteomics reveals novel combinatorial histone modification signatures that mark distinct subpopulations of macrophage enhancers

Project description:The integrated activity of cis-regulatory elements fine-tunes transcriptional programs of mammalian cells by recruiting cell type–specific as well as ubiquitous transcription factors (TFs). Despite their key role in modulating transcription, enhancers are still poorly characterized at the molecular level, and their limited DNA sequence conservation in evolution and variable distance from target genes make their unbiased identification challenging. The coexistence of high mono-methylation and low tri-methylation levels of lysine 4 of histone H3 is considered a signature of enhancers, but a comprehensive view of histone modifications associated to enhancers is still lacking. By combining chromatin immunoprecipitation (ChIP) with mass spectrometry, we investigated cis-regulatory regions in macrophages to comprehensively identify histone marks specifically associated with enhancers, and to profile their dynamics after transcriptional activation elicited by an inflammatory stimulation. The intersection of the proteomics data with ChIP-seq and RNA-seq analyses revealed the existence of novel subpopulations of enhancers, marked by specific histone modification signatures: specifically, H3K36me2/K4me1 marks transcribed enhancers, while H3K36me3/K4me1 and H3K79me2/K4me1 combinations mark distinct classes of intronic enhancers. Thus, our MS analysis of functionally distinct genomic regions revealed the combinatorial code of histone modifications, highlighting the potential of proteomics in addressing fundamental questions in epigenetics.

2017-10-09 | PXD007582 | Pride

ChIP-Seq data from IMR90 Control and IMR90 HRAS-G12V using an H3K79me3 antibody

Project description:Oncogene-induced senescent cells display a robust change in their epigenome and have increased transcription and secretion of numerous pro-inflammatory cytokines and chemokines termed the senescence-associated secretory phenotype (SASP). Therefore, understanding how and if the epigenome is involved in regulating the transcription of the SASP is critical to understanding how to restrain the harmful effects of the SASP. The active histone marks H3K79me2 and H3K79me3 and their methyltransferase DOT1L are increased during oncogene-induced senescence. Whether H3K79 methylation and DOT1L expression are involved in the transcriptional regulation of the SASP is unknown.

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Gene expression data from IMR90 Control, IMR90 HRAS-G12V, IMR90 HRAS-G12V+shDOT1L, IMR90 DOT1L Overexpression

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A novel chemical biology high-content strategy for the identification of novel HMT inhibitors reveals a crosstalk between DOT1L and CARM1

Project description:Epigenetic regulation is a dynamic and reversible process that controls gene expression. Abnormal function results in downregulation or upregulation of pathways leading to diseases, such as cancer. The enzymes that establish and maintain epigenetic marks, such as histone methyltransferases (HMTs), are therapeutic targets as their and, importantly, the epigenetic modifications are reversible. Noteworthy, HMTs, as the other epigenetic enzymes and readers, form together multiprotein complexes that in concert regulate histone marks. To probe the epigenetic protein complexes in a biological system, we developed a reliable chemical biology high-content imaging strategy to screen compound libraries on multiple histone marks inside cells simultaneously. The advantage is double: (1) it identifies directly a drug that is active in cells on a specific histone mark and (2) it reveals the crosstalk between the epigenetic marks. By this approach, we identified that compound 4, a published CARM1 (PRMT4) inhibitor, inhibits both histone mark H3R2me2a (regulated by CARM1) and H3K79me2 (regulated by DOT1L) pointing out a synergistic interaction between the two HMTs. The results obtained by the screening assay were validated by mass spectrometry and other techniques confirming the crosstalk between the two marks and HMTs. Prompted by the interaction between CARM1 and DOT1L we combined compound 4 and DOT1L inhibitor EPZ-5676 resulting in a stronger cell proliferation inhibition and apoptosis, indicating that our approach provides also a novel strategy to identify effective synergistic drug combinations for cancer therapy.

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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

DOT1L Inhibits SIRT1 and SUV39H1-Mediated H3K9 Modification to Maintain Gene Expression (array)

Project description:Methylation of histone 3 on lysine 79 (H3K79) is broadly associated with active gene expression in eukaryotes, and the H3K79 methyltransferase DOT1L is indispensable for specific leukemia subtypes like those with MLL-translocations. We found that suppression of the histone deacetylase SIRT1 rescued MLL-AF9 leukemia cells from their dependence on DOT1L. We show that upon DOT1L inhibition, SIRT1 is required for the acquisition of a repressive chromatin state consistent with facultative heterochromatin around MLL-AF9 target genes in leukemia and other genes possess an H3K79me2(hi), H3K9ac(hi), H3K9me2(low) histone modification profile in normal hematopoietic stem and progenitor cells. Examination of gene expression dynamics with and without drug treatment and RNA interference.

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