PML is a novel constitutive component of chromatin domains of enriched repetitive elements and duplicated gene clusters in cancer cells
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ABSTRACT:
PROVIDER: PRJNA1089597 | ENA |
REPOSITORIES: ENA
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Project description:Heterochromatin is a pivotal element in the functional organization of genomes. In our study, we delve into the heterochromatin pattern of association by the PML (promyelocytic leukemia) protein. By using PML chromatin immunoprecipitation and sequencing data and comparing computational methodologies to depict PML chromatin association, we describe PML-associated domains or PADs as large heterochromatic regions that exhibit similar genomic features across cancer cell lines. We show that PADs are specifically enriched in non-coding genes, duplicated gene clusters, and repetitive DNA elements. Moreover, we find enriched binding motifs of KZFPs, which are involved in orchestrating epigenetic repression at repetitive DNA elements. Hence, our findings suggest that PML conservatively associates to heterochromatic domains enriched in repetitive DNA elements and duplicated gene clusters in cancer. These findings contribute to a broader understanding of the complex regulatory framework of genome organization by heterochromatin in cancer.
2024-08-22 | GSE261929 | GEO
Project description:Identifying the functions of proteins, which define specific subnuclear structures and territories, is important for understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML bodies and co-localizes with the proto-oncogenic protein PML and Daxx, proteins with critical roles in oncogenic transformation, interferon-mediated viral resistance and response to PML-directed cancer therapeutics. Sp100 isoforms contain PHD, Bromo and HMG domains and are highly sumoylated at ND10/PML bodies, all characteristics suggestive of a role in chromatin mediated gene regulation. However, no clear role for the Sp100 component of PML bodies in oncogenesis has been defined. Using isoform-specific knockdown techniques, we show that most human diploid fibroblasts, which lack Sp100, rapidly senesce and discuss gene expression changes associated with this rapid senescence.
2012-12-04 | GSE20613 | GEO
Project description:The Sp100 component of ND10/PML bodies is a potent tumor suppressor: accelerated senescence and rapid malignant transformation of human fibroblasts through modulation of an embryonic stem cell program. Identifying the functions of proteins, which define specific subnuclear structures and territories, is important for understanding eukaryotic nuclear dynamics. Sp100 is a prototypical protein of ND10/PML bodies and colocalizes with the proto-oncogenic protein PML and Daxx, proteins with critical roles in oncogenic transformation, interferon-mediated viral resistance and response to PML-directed cancer therapeutics. Sp100 isoforms contain PHD, Bromo and HMG domains and are highly sumoylated at ND10/PML bodies, all characteristics suggestive of a role in chromatin mediated gene regulation. However, a clear role for Sp100 in oncogenesis has not been defined. Using isoform-specific knockdown techniques, we show that most human diploid fibroblasts, which lack Sp100, rapidly senesce. microarray analysis of mRNAs expression in BJV (collected at passage 47) and BJ-S (collected at passage 35). In addition, samples were treated for 24 h with 1000 U/ml IFNB. All RNAs were collected in triplicates of biological samples.
2012-12-04 | E-GEOD-20613 | biostudies-arrayexpress
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference betweem Pml wt and Pml KO under fasted condition, which easily up-regulate ROS in BALB/cByJ background
2017-09-22 | GSE100615 | GEO
Project description:The Pml gene is essential to the formation of PML nuclear bodies, domains which have been associated with various functions such as apoptosis/senescence, DNA repair and cell proliferation( Lallemand-Breitenbach 2010). PML-NBs formation is regulated by cellular stress including oxidative stress(Jeanne 2010, de The 2012). To investigate the role of PML in ROS response in vivo, we analyse the expression difference to the acetaminophen toxicity, which is initiated by ROS, in Pml wt and Pml KO mice.
2017-09-22 | GSE100616 | GEO
Project description:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients. Bone marrow from individual mice expressing PML-RARA from the murine Ctg locus (mCG-PR) and littermate controls was harvested from both femurs and tibia. Standard cell lysis was performed, and total RNA was extracted from the cells and analyzed using the Affymetrix Mouse Exon 1.0 ST platform.
2012-08-13 | E-GEOD-40022 | 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:Because PML-RARA-positive acute promyelocytic leukemia (APL) is a morphologically differentiated leukemia, much speculation has been made about whether its leukemic cell of origin might be committed myeloid precursor (e.g., a promyelocyte) vs. a hematopoietic stem/progenitor cell (HSPC). We originally targeted PML-RARA expression with CTSG regulatory elements, based on the early observation that this gene was maximally expressed in cells with promyelocyte morphology. Here, we show that both Ctsg and PML-RARA targeted to the Ctsg locus (in Ctsg-PML-RARA mice) are detected in the purified KLS cells of these mice (Kit+Lin-Sca+ cells, which are highly enriched for HSPCs), and this expression results in biological effects in multi-lineage competitive repopulation assays. Although PML-RARA is indeed expressed at high levels in the promyelocytes of Ctsg-PML-RARA mice, it does not significantly alter the transcriptional signature of these cells, or induce their self-renewal. In sum, these results suggest that in murine models, PML-RARA acts primarily to affect the function of multi-potent progenitor cells, rather than promyelocytes. Since PML/Pml is normally expressed in the HSPCs of both humans and mice, and since some human APL samples contain TCR rearrangements and express T lineage genes, we suggest that the very early hematopoietic expression of PML-RARA in our mouse model may closely mimic the physiologic expression pattern of PML-RARA in human APL patients.
2012-08-14 | GSE40022 | GEO
Project description:Transcriptional profiling of murine cells expressing PML/RARA at the early promyelocyte stage (4 weeks old, preleukemic) and in full blown PML/RARA leukemia generated by transducing PML/RARA bone marrow with a Flt3-ITD retroviral vector
2015-07-15 | GSE59431 | GEO
Project description:The promyelocytic leukemia (PML) body is a phase-separated nuclear structure composed of various proteins including several chromatin regulators, and physically associates with chromatin. To address functional roles of the PML-chromatin association, we conducted genome-wide profiling of PML body-associated regions.
2019-08-14 | GSE135560 | GEO