Chromatin accessibility, p300 and histone acetylation define PML-RARalpha- and AML1-ETO-binding sites
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE30254 | GEO | 2012/08/29
SECONDARY ACCESSION(S): PRJNA143747
REPOSITORIES: GEO
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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
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
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
Project description:The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.
| S-EPMC3251012 | biostudies-literature
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
Project description:AML1-ETO is the chimeric protein product of t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the nervy homology region (NHR) 3 domain, which shares homology with A-kinase anchoring proteins and interacts with the regulatory subunit of type II cAMP-dependent protein kinase A (PKA(RII?)). We determined the solution structure of a complex between the AML1-ETO NHR3 domain and PKA(RII?). Based on this structure, a key residue in AML1-ETO for PKA(RII?) association was mutated. This mutation did not disrupt AML1-ETO's ability to enhance the clonogenic capacity of primary mouse bone marrow cells or its ability to repress proliferation or granulocyte differentiation. Introduction of the mutation into AML1-ETO had minimal impact on in vivo leukemogenesis. Therefore, the NHR3-PKA(RII?) protein interaction does not appear to significantly contribute to AML1-ETO's ability to induce leukemia.
| S-EPMC2945414 | biostudies-literature
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
Project description:AML1-ETO is the chimeric protein product of the t(8;21) in acute myeloid leukemia. The ETO portion of the fusion protein includes the eTAFH domain, which is homologous to several TATA binding protein-associated factors (TAFs) and interacts with E proteins (E2A and HEB). It has been proposed that AML1-ETO-mediated silencing of E protein function might be important for t(8;21) leukemogenesis. Here, we determined the solution structure of a complex between the AML1-ETO eTAFH domain and an interacting peptide from HEB. On the basis of the structure, key residues in AML1-ETO for HEB association were mutated. These mutations do not impair the ability of AML1-ETO to enhance the clonogenic capacity of primary mouse bone marrow cells and do not eliminate its ability to repress proliferation or granulocyte differentiation. Therefore, the eTAFH-E protein interaction appears to contribute relatively little to the activity of AML1-ETO.
| S-EPMC2668852 | biostudies-literature
Project description:AML1-ETO fusion protein (AE) is generated by t(8;21)(q22;q22) chromosomal translocation, which is one of the most frequently observed structural abnormalities in acute myeloid leukemia (AML) and displays a pivotal role in leukemogenesis. The histone acetyltransferase p300 promotes self-renewal of leukemia cells by acetylating AE and facilitating its downstream gene expression as a transcriptional coactivator, suggesting that p300 may be a potential therapeutic target for AE-positive AML. However, the effects of p300 inhibitors on leukemia cells and the underlying mechanisms have not been extensively investigated. In the current study, we analyzed the anti-leukemia effects of C646, a selective and competitive p300 inhibitor, on AML cells. Results showed that C646 inhibited cellular proliferation, reduced colony formation, evoked partial cell cycle arrest in G1 phase, and induced apoptosis in AE-positive AML cell lines and primary blasts isolated from leukemic mice and AML patients. Nevertheless, no significant inhibitory effects were observed in granulocyte colony-stimulating factor-mobilized normal peripheral blood stem cells. Notably, AE-positive AML cells were more sensitive to lower C646 doses than AE-negative ones. And C646-induced growth inhibition on AE-positive AML cells was associated with reduced global histone H3 acetylation and declined c-kit and bcl-2 levels. Therefore, C646 may be a potential candidate for treating AE-positive AML.
| S-EPMC3563640 | biostudies-literature
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