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Homo sapiens

ABSTRACT: Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [human]

PROVIDER: PRJNA343074 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR4244130.fastq.gz	Fastqsanger.gz
	SRR4244140.fastq.gz	Fastqsanger.gz
	SRR4244150.fastq.gz	Fastqsanger.gz
	SRR4244160.fastq.gz	Fastqsanger.gz
	SRR4244170.fastq.gz	Fastqsanger.gz

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Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers

Project description:Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers

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Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [mouse]

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Rational targeting of cooperating layers of the epigenome yields enhanced therapeutic efficacy against AML

Project description:Disruption of epigenetic regulation is a hallmark of Acute Myeloid Leukemia (AML), but therapeutic interventions are difficult by the interplay of epigenetic mechanisms controlling genomic elements. We hypothesized that concurrent targeting of aberrant promoter and enhancer epigenetic silencing improves efficacy against AML. To test this, we developed an ex vivo culturing system and treated 52 patient-derived AML with low-dose 5-Azacytidine and specific LSD1 inhibitors. Genetic analysis revealed that combination of 5-Azacytidine and LSD1 inhibition was most effective in TET2mut AML. Combination therapy further up-regulated expression of genes associated with both LSD1-bound enhancers and cytosine methylated promoters. Functional validation studies suggest that expression of these genes (e.g. GATA2, GFI1 and DLX2) contribute to drug efficacy. Mechanistically, combination therapy increased enhancer-promoter looping and chromatin-activating marks at the GATA2 locus. This gene induction effect was dampened by CRISPRi of the LSD1-bound enhancer in TET2mut AML. Concordant with TET2mut AML, knockdown of TET2 in human hematopoietic stem and progenitor cells induced loss of enhancer 5-hydroxymethylation and facilitated LSD1-mediated enhancer inactivation. Collectively, our platform revealed increased LSD1-mediated enhancer inactivation after TET2 deficiency that provided a basis for combinatorial epigenetic therapy to activate promoter-enhancer interactions.

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TINC - a method to dissect transcriptional complexes at single locus resolution - reveals novel Nanog regulators in mouse embryonic stem cells

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2020-12-14 | PXD022088 | Pride

Trim33 binds and silences a class of young endogenous retroviruses in the mouse testis

Project description:Transposable elements (TEs) have been active in the mammalian genome for hundreds of millions of years and each TE has had a distinct period of transpositional activity, followed by inactivation. Mice carrying reporter transgenes can be used to model transcriptional silencing at TEs. A mutagenesis screen for modifiers of epigenetic gene silencing produced a line with a null mutation in Trim33. Heterozygous mutants displayed increased expression of the reporter transgene. ChIP-seq of Trim33 in testis revealed 9,109 peaks, mostly at promoters, across the mouse genome. Trim33 was enriched at many RLTR10B elements that are among the youngest retrotransposons in the mouse genome. RNA-seq revealed that testis of mice haploinsufficient for Trim33 had altered expression of a small group of genes. The gene with the most significant increase, Nmnat3, was found to be transcribed from an upstream RLTR10B element. We show that Trim33 is involved in repressing RLTR10B elements in mouse testis. Examination of Trim33 binding using ChIP sequencing and the result of Trim33 haploinsufficiency using RNA sequencing, in mouse testis

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2016-02-01 | E-GEOD-55770 | biostudies-arrayexpress

Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis (Affymetrix)

Project description:DNA methylation is tightly regulated throughout mammalian development and altered methylation patterns are a hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in acute myeloid leukemia (AML) and has been suggested to protect CpG islands and promoters from aberrant methylation. By generating a novel mouse model of Tet2-deficient AML we show that loss of Tet2 in hematopoietic cells leads to progressive hypermethylation of active enhancer elements and altered expression of genes implicated in tumorigenesis. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner. Furthermore, we confirm this specific enhancer hypermethylation phenotype in human AML patients. Thus, we propose that TET2 prevents leukemic transformation of hematopoietic cells by protecting enhancers from aberrant DNA methylation. Gene expression profiles from Tet2-/-;AML1-ETO and Tet2fl/fl;AML1-ETO in vitro-grown hematopoietic cells were compared using GeneChip Mouse Gene ST 2.0 Arrays (Affymetrix). Expression changes were investigated at early (passage 2) and late (passage 10) timepoints after Tet2 disruption.

2015-04-22 | E-GEOD-59586 | biostudies-arrayexpress

miR-495 regulates multiple epigenetic modifiers in gastric cancer

Project description:Revealing Dominant Regulatory MicroRNA-495-3p that Governs Multiple Epigenetic Modifiers in Gastric Carcinogenesis In this study, we identified miR-495-3p targeting multiple epigenetic modifiers through comprehensive miRNA and mRNA profiling analysis with in silico target prediction in GC. Western blotting assay or quantitative real time PCR was performed to confirm the expression of miR-495-3p and targets of it. We applied miRNA mimics to ectopic overexpression in gastric cancer cells and observed tumor suppressive effects of miR-495-3p in the growth and metastasis of cancer. Also, we confirmed the status of CpG islands of miR-495-3p promoter using methylation specific PCR analysis.

2015-09-18 | E-GEOD-67354 | biostudies-arrayexpress

Epigenetic identity in AML is mostly dependent on disruption of non-promoter regulatory elements and reveals potentially antagonistic effects of mutations in epigenetic modifiers [mouse]

Project description:Aberrant DNA methylation of gene promoters is a hallmark of AML. To define more precisely how cytosine methylation is redistributed in AML, we performed base-pair resolution methylome sequencing in 119 patients. We find that leukemic DNA methylation patterning is tightly linked to somatic mutations and primarily driven by regulatory elements outside of promoters and by CpG shores as opposed to CpG islands. Active enhancers displayed much stronger focal differential methylation than promoters and were generally aberrantly hypomethylated except in IDH2 mutant and CEBPA silenced AMLs. AMLs with dominant hypermethylation feature greater epigenetic disruption of promoters. Those with dominant hypomethylation, such as DNMT3A mutated AMLs, display greater disruption of distal and intronic regions. IDH mutant AMLs manifest profound hypermethylation whereas DNMT3A mutant AMLs manifest profound hypomethylation of a different set of CpGs. In striking contrast, AMLs with co-occurring IDH1 and DNMT3A mutations exhibited epigenetic antagonism in which most CpGs affected by either mutation alone were no longer affected in the double mutant cases.

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Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy

Project description:This SuperSeries is composed of the SubSeries listed below. Deep sequencing has revealed that epigenetic modifiers are the most mutated genes in acute myeloid leukemia (AML). Thus, elucidating epigenetic dysregulation in AML is crucial to understand disease mechanisms. Here, we demonstrate that Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in the Polycomb repressive complex 2 (PRC2) and that its loss elicits an altered epigenetic state underlying refractory AML. Unbiased systems analyses identified the loss of MTF2-PRC2 repression of MDM2 as central to, and therefore a biomarker for, refractory AML. Thus, immature MTF2- deficient CD34+CD38- cells overexpress MDM2, thereby inhibiting p53 that leads to chemoresistance due to defects in cell cycle regulation and apoptosis. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.

2018-07-31 | GSE98380 | GEO

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