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Gene expression profiling of cancer cells with genetic disruption of DNA methyltransferases [Agilent-014850]

ABSTRACT: Maximizing DNA methyltransferase (DNMT’s) inhibition for cancer therapy requires defining the roles and interactions between these enzymes for maintaining the widespread DNA methylation abnormalities in cancer. Combining genetic and shRNA depletion in colon and other cancer cells reveals that DNMT1 is extremely dominant in this maintenance, with DNMT’s 3A and 3B playing minor roles, at all genomic loci including promoters and enhancers. Reducing DNMT1 below a deep threshold level, especially at promoters, is required for reversing abnormal DNA methylation and re-expressing key tumor suppressor genes. Current DNMT inhibitors (DNMTis) are challenged, at tolerable patient doses, for achieving such reductions. We introduce a new approach in which reducing levels of the DNMT targeting protein, UHRF1, complements low DNMTi doses to DNA demethylate and reactivate expression of such genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE93142 | GEO | 2017/01/13

SECONDARY ACCESSION(S): PRJNA360127

REPOSITORIES: GEO

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DNA methylation profiling of cancer cells with genetic disruption of DNA methyltransferases

Project description:Maximizing DNA methyltransferase (DNMT’s) inhibition for cancer therapy requires defining the roles and interactions between these enzymes for maintaining the widespread DNA methylation abnormalities in cancer. Combining genetic and shRNA depletion in colon and other cancer cells reveals that DNMT1 is extremely dominant in this maintenance, with DNMT’s 3A and 3B playing minor roles, at all genomic loci including promoters and enhancers. Reducing DNMT1 below a deep threshold level, especially at promoters, is required for reversing abnormal DNA methylation and re-expressing key tumor suppressor genes. Current DNMT inhibitors (DNMTis) are challenged, at tolerable patient doses, for achieving such reductions. We introduce a new approach in which reducing levels of the DNMT targeting protein, UHRF1, complements low DNMTi doses to DNA demethylate and reactivate expression of such genes.

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Gene expression profiling of cancer cells with genetic disruption of DNA methyltransferases [Agilent-026652]

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Base-editor-mediated multiplexed inactivation of DNA methyltransferases reveals essential roles of miRNAs in mouse gastrulation

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Regulation of Promoter and Enhancer Histone Landscape by DNA Methylation in Embryonic Stem Cells (RNA-seq)

Project description:In this study, we mapped modification of lysine 4 and lysine 27 of histone H3 genome-wide in a series of mouse embryonic stem cells (mESCs) varying in DNA methylation levels based on knock-out and reconstitution of DNA methyltransferases (DNMTs). We extend previous studies showing cross-talk between DNA methylation and histone modifications by examining a breadth of histone modifications, causal relationships, and direct effects. Our data shows a causal regulation of H3K27me3 at gene promoters as well as H3K27ac and H3K27me3 at tissue-specific enhancers. We also identify isoform differences between DNMT family members. This study provides a comprehensive resource for the study of the complex interplay between DNA methylation and histone modification landscape. RNA-seq performed on wild-type, Dnmt triple knock-out (Dnmt1/3a/3b; TKO), Dnmt double knock-out (Dnmt3a/3b; DKO), and respective reconstitution mouse embryonic stem cell lines

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RRBS profiling of mouse ESCs (wild type and DNMT KOs)

Project description:DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Somatic patterns of DNA methylation are largely static, apart from focal dynamics at gene regulatory elements. To further advance our understanding of the role of DNA methylation in human development and disease, we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death, demonstrating that DNA methylation is essential for human ESCs cultured in standard conditions. In summary, our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets. RRBS profiling of mouse ESCs (wild type and DNMT KOs)

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Histone ubiquitination-methylation crosstalk involving UHRF1 and SUV39H1/2 reinforces heterochromatin states in response to DNA hypomethylation

Project description:Histone H3 mono-ubiquitination, catalyzed by the RING E3 ubiquitin ligase UHRF1, is appreciated as a docking site for DNMT1 during DNA replication to facilitate DNA methylation maintenance. Its functions beyond this are unknown. Here, we identify simultaneous increases in UHRF1-dependent H3K18ub and SUV39H1/2-dependent H3K9me3 as prominent epigenetic alterations accompanying DNA hypomethylation induced by DNMT1 inhibition. Integrative epigenomics analyses reveal that transient accumulation of hemi-methylated DNA, resulting from incomplete DNA methylation maintenance, stimulates UHRF1-dependent H3K18ub at CpG islands that nucleates new domains of H3K9me3 and impedes PRC2 activity in these genomic regions. Notably, H3K18ub enhances the methyltransferase activity of SUV39H1/2, leading to increased H3K9me3 at these CpG island promoters. Blocking H3K18ub-dependent SUV39H1/2 activity enhances the efficacy of DNMT1 inhibitors. Collectively, these findings reveal a novel histone ubiquitination-methylation crosstalk mechanism that reinforces heterochromatin states in the absence of DNA methylation and proposes new strategies for improving cancer epigenetic therapy.

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