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Chromatin accessibility, p300 and histone acetylation define PML-RARalpha- and AML1-ETO-binding sites

ABSTRACT: Chromatin accessibility is a key determinant of cell-type-specific gene expression. Here, we have investigated the chromatin architecture of different acute myeloid leukemia (AML) cells and the changes in accessibility when NB4 (APL) cells undergo the process of differentiation.

ORGANISM(S): Homo sapiens

PROVIDER: GSE30254 | GEO | 2012/08/29

SECONDARY ACCESSION(S): PRJNA143747

REPOSITORIES: GEO

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Chromatin accessibility, p300 and histone acetylation define PML-RARalpha- and AML1-ETO-binding sites

Project description:Chromatin accessibility is a key determinant of cell-type-specific gene expression. Here, we have investigated the chromatin architecture of different acute myeloid leukemia (AML) cells and the changes in accessibility when NB4 (APL) cells undergo the process of differentiation. For nuclease-accessible site sequencing (NA-seq; Gargiulo et al. 2009), chromatin-accessible libraries were generated in different AML leukemic cells by using restriction enzymes NlaIII and HpaII. In the case of NB4 cells, accessibility was mapped both before and after treatment with all-trans retinoic acid (ATRA) for 48hr. Differences were observed between the two conditions, and chromatin accessibility was correlated with underlying epigenetic modifications. For validation purposes, NA-seq libraries (using the NlaIII enzyme) were generated in APL and AML M1 patient's blasts. All of the ChIP-seq (Martens et al. 2010) studies were performed in leukemic NB4 and SKNO-1 cells. Supplementary file 'GSE30254_All_accessibleregions_ATRA_NB4_fseq.wig' includes data for Samples GSM749512, GSM749513, GSM749516, and GSM749517. Supplementary file 'GSE30254_All_accessibleregions_untreated_NB4_fseq.wig' includes data for Samples GSM749510, GSM749511, GSM749514, and GSM749515.

2012-08-29 | E-GEOD-30254 | biostudies-arrayexpress

Genome-wide studies identify genes directly regulated by PML/RARα fusion protein

Project description:Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosome translocation that generates the promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion gene. However, the global association between PML/RARα and transcriptional co-regulators, and the rules of their association in governing the key processes during the leukemogenesis remain obscure. Here, we performed the genome-wide binding profiling of PML/RARα, HDAC1 and P300, in NB4, an APL patient-derived cell line. We found that PML/RARα targets could be classified into two classes. Moreover, we also performed ChIP-seq of H3K27ac to determine super-enhancers in NB4. We identified a novel function of PML/RARα in super-enhancer regulation during the leukemogenesis of APL.

2020-08-26 | GSE126720 | GEO

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Project description:Epigenetic abnormalities are frequently involved in the initiation and progression of cancers including acute myeloid leukemia (AML). A subtype of AML, Acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of PML-RARα. PML-RARα was reported as a transcription repressor through the interaction with NCoR/HDAC complexes leading to the mis-suppression of its target genes and differentiation blockage. While previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri- methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, we detected KDM5A binding in 1,889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes primarily by controlling the H3K4me2 in the promoters and 5’ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455 on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to ATRA induced differentiation. Our findings indicated that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.

2021-04-01 | GSE152397 | GEO

The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.

Project description: Not available

| S-EPMC3251012 | biostudies-literature

PML-RARa binding sites and their correlation with the gene expression in ATRA treated NB4 cells

Project description:PML-RARa contributes to the development of APL through repression of genes important in myeloid development. Through a global approach, we have identified 2,979 high quality PML-RARa binding sites in ZnSO4 induced PR9 cells. By integration the gene expression data, we found that PML/RARa target genes are transcriptionally suppressed in primary APL cells and re-activated in ATRA treated NB4 cells. This SuperSeries is composed of the SubSeries listed below.

2009-11-26 | GSE19203 | GEO

Genome-wide epigenetic analyses and Transcriptional analysis in NB4 cells expressing PML-RARalpha

Project description:Illumina High-Throughput ChIP Sequencing profiling was performed using the H3K9K14ac antibody in NB4 cells treated with the compounds ATRA, MS-275,MC2392 (a hybrid molecule of ATRA with a 2-aminoanilide tail of the HDAC inhibitor MS-275) or solvent, DMSO. We find that MC2392 induces changes in H3 acetylation at a small subset of PML-RARα binding sites but also in regions not regulated by ATRA. Moreover, MC2392 alters expression of a number of stress-responsive and apoptotic genes.

2016-09-17 | GSE50958 | GEO

Structure of the AML1-ETO NHR3-PKA(RII?) complex and its contribution to AML1-ETO activity.

Project description: Not available

| S-EPMC2945414 | biostudies-literature

Structure of the AML1-ETO eTAFH domain-HEB peptide complex and its contribution to AML1-ETO activity.

Project description: Not available

| S-EPMC2668852 | biostudies-literature

A histone acetyltransferase p300 inhibitor C646 induces cell cycle arrest and apoptosis selectively in AML1-ETO-positive AML cells.

Project description: Not available

| S-EPMC3563640 | biostudies-literature

Expression profiling of ATRA treated NB4 cells

Project description:NB4 is an APL derived cell line, carrying the t(15;17) translocation and expressing the PML/RARa fusion protein. Still, an important question that remains to be addressed is whether PML/RARa target genes are transcriptionally suppressed in primary APL cells and re-activated in all-trans retinoic acid (ATRA) treated NB4 cells. Gene expression of NB4 cells treated with ATRA at different time points were analyzed.

2009-11-26 | GSE19201 | GEO

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