Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia (ChIA-PET)
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PROVIDER: PRJNA566172 | ENA |
REPOSITORIES: ENA
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Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-05 | GSE137661 | GEO
Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-17 | GSE142198 | GEO
Project description:Acute promyeloid leukemia (APL) is characterized by the oncogenic fusion protein PML/RARα, a major etiological agent in APL. Although PML/RARα is critical, the molecular mechanisms remains largely unknown. Here, using an inducible system, we comprehensively analyzed the 3D genome organization in myloid cells and its reorganizationn after PML/RARα induction, and performed additional analysis in patient-derived APL cells with native PML/RARα. We discovered that PML/RARα mediate extensive chromatin interactions genome-wide. Globally, it redefine the chromatin topology of the in myloid genome toward a more condensed configuration in APL cells; locally, it intrude RNAPII-associated interaction dmains, interrupt myeloid-specific transcription factors binding at enhancers and super-enahncers, and lead to transcriptional repression of genes critical for myeloid differentiation and maturation. Together, our results provide novel insights of a topological framework for PML/RARα’s roles in transforming myeloid into leukemia, likely a general mechanism for oncogenic fusion proteins in cancers.
2019-12-17 | GSE142197 | GEO
Project description:The pluripotent state of embryonic stem cells (ESCs) is produced by active transcription of cell identity genes and repression of genes encoding lineage-specifying developmental regulators. Here we use large ESC cohesin ChIA-PET datasets and other genomic data to identify the local chromosomal structures at both active and repressed genes across the genome. The results show that super-enhancer driven cell identity genes generally occur within large loops that are connected through CTCF-CTCF interaction sites occupied by cohesin. Smc1 ChIA-PET data from wild type murine embryonic stem cells V6.5 were generated by deep sequencing using Illumina Hi-Seq 2000.
2014-06-27 | E-GEOD-57911 | biostudies-arrayexpress
Project description:We defined the RARα interactome in the MDA-MB453 breast cancer cell line genetically engineered to over-express an N-terminally tagged version of the nuclear retinoic acid receptor. Twenty eight nuclear proteins which interact with RARα and whose interaction is stimulated or reduced by the pan-RAR ligand, all-trans retinoic acid (ATRA) were identified. Given the potential significance of the S100A3 calcium-binding protein in the control of tumor progression, we focused our attention on this factor. Using the two models represented by the ATRA-sensitive SKBR3 and MCF7 breast cancer cell lines characterized by constitutive expression of S100A3 and RARα, we demonstrate that the endogenous forms of S100A3 and RARα interact in physiological conditions. The interaction of S100A3 with RARα is cell context independent and it is observed not only in breast cancer but also in acute promyelocytioc leukemia (APL) cells, characterized by expression of the RARα-derived PML-RARα oncogene, which is the product of the t(15:17) chromosomal translocation. S100A3 interacts directly and specifically with RARα and PML-RARα, being unable to bind other members of the RAR/RXR family of retinoid nuclear receptors. The interaction surface maps to the carboxyl-terminal region of the RARα ligand binding domain. Binding of S100A3 to RARα and PML-RARα controls the constitutive and ATRA-dependent degradation of the two receptors. Silencing of the S100A3 gene decreases the amounts of RARα in breast SK-BR-3 and lung A549 cancer cells, rendering them more refractory to the anti-proliferative action of ATRA. In SK-BR-3 cells, this effect is accompanied by a decrease in the lactogenic/differentiating action of ATRA. In APL-derived NB4 cells, S100A3 knock-down reduces the amounts of both RARα and PML-RARα. Contemporaneous down-regulation of the two receptors is associated with an increase in the basal and ATRA-induced expression of many granulocytic differentiation markers. Opposite on RARα and PML-RARα levels as well as ATRA induced differentiation markers are observed upon over-expression of S100A3 in NB4 cells.
2019-12-18 | PXD008761 | Pride
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:This data was generated by ENCODE. If you have questions about the data, contact the submitting laboratory directly (Yijun Ruan mailto:ruanyj@gis.a-star.edu.sg). If you have questions about the Genome Browser track associated with this data, contact ENCODE (mailto:genome@soe.ucsc.edu). This track was produced as part of the ENCODE Project. It shows the locations of protein factor mediated chromatin interactions determined by Chromatin Interaction Analysis with Paired-End Tag (ChIA-PET) data (Fullwood et al., 2010) extracted from five different human cancer cell lines (K562 (chronic myeloid leukemia), HCT116 (colorectal cancer), HeLa-S3 (cervical cancer), MCF-7 (breast cancer), and NB4 (promyelocytic)). A chromatin interaction is defined as the association of two regions of the genome that are far apart in terms of genomic distance, but are spatially proximate to each other in the 3-dimensional cellular nucleus. Additionally, ChIA-PET experiments generate transcription factor binding sites. A binding site is defined as a region of the genome that is highly enriched by specific Chromatin ImmunoPrecipitation (ChIP) against a transcription factor, which indicates that the transcription factor binds specifically to this region. The protein factors displayed in the track include estrogen receptor alpha (ERa), RNA polymerase II (RNAPII), and CCCTC binding factor (CTCF). For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf Chromatin interaction analysis with paired-end tag sequencing (ChIA-PET) is a global de novo high-throughput method for characterizing the 3-dimensional structure of chromatin in the nucleus. In the ChIA-PET protocol, samples were cross-linked and fragmented, then subjected to chromatin immunoprecipitation. The DNA fragments that were brought together by the chromatin interactions were then proximity-ligated. During this proximity-ligation step, the half-linkers (created by the fragmentation) containing flanking MmeI sites (type IIS restriction enzymes) were first ligated to the DNA fragments and then ligated to each other to form full linkers. Full linkers bridge either two ends of a self-circularized fragment, or two ends of two different chromatin fragments. The material was then reverse cross-linked, purified and digested with MmeI. MmeI cuts 20 base pairs away from its recognition site. Tag-linker-tag (paired-end tag, PET) constructs were sequenced by ultra-high-throughput methods (Illumina or SOLiD paired-end sequencing). ChIA-PET reads were processed with the ChIA-PET Tool (Li et al., 2010) by the following steps: linker filtering, short reads mapping, PET classification, binding site identification, and interaction cluster identification. The high-confidence binding sites and chromatin interaction clusters were reported. Chromatin interactions identified by ChIA-PET have been validated by 3C, ChIP-3C, 4C and DNA-FISH (Fullwood et al., 2009).
2012-07-19 | E-GEOD-39495 | biostudies-arrayexpress
Project description:Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia. DNA methylation profiling in CD34(+) early promyelocytes and CD34(-) late promyelocytes cells from PML-RARa transgenic mice vs. control mice.
2015-09-04 | E-GEOD-54038 | biostudies-arrayexpress
Project description:Chromatin Topology Reorganization and Transcription Repression by PML/RARα in Acute Promyeloid Leukemia
| PRJNA566168 | ENA
Project description:Acute Promyelocytic Leukemia is characterized by the accumulation in the blood and bone marrow of promyelocytes. The PML/RARα fusion protein is identified as the primary abnormality implicated in the pathology, and is believed to prevent transcription of genes necessary for normal myeloid development and differentiation. Identifying its targets is critical to comprehend the road to pathogenesis. To understand how PML/RARα, in the absence of secondary lesions, alters gene expression, DNA methylation and proliferation we used a novel experimental and sorting strategy to study normal versus preleukemic promyelocytes in vivo. Expression and methylation profiling analyses were performed on highly purified samples. Surprisingly, despite its ability to initiate leukemia, PML/RARα had overall minor effects on both the transcriptome and epigenome. Important regulators of the myeloid maturation program were not altered but, remarkably, PML/RARα promyelocytes showed strong downregulation of secondary and tertiary granule genes. Subtle changes were also observed on the DNA methylation profile, with PML/RARα predominantly mediating hypomethylation. We performed intersection studies between altered loci and previously described PML/RARα binding sites but found little overlap. Importantly, we show for the first time that PML/RARα on its own increases proliferation, and that this increased proliferation correlates with the ability to initiate leukemia.
2015-09-04 | GSE54038 | GEO