41 results on '"Maleszewska M"'
Search Results
2. Hypoxia promotes osteogenesis via regulation of the mito-nuclear communication
- Author
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Pouikli, A., Maleszewska, M., Parekh, S., Nikopoulou, C., Bonfiglio, J., Mylonas, C., Sandoval, T., Hinze, Y., Matić, I., and Tessarz, P.
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- 2022
3. Epigenetic control of microglia polarization in brain pathologies: S15-01
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Kaminska, B., Maleszewska, M., Steranka, A., and Smiech, M.
- Published
- 2015
4. Jmjd3 is a novel target of Stat1 and Stat3 which cooperate to drive inflammatory genes expression in LPS-stimulated microglia: P21-86
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Przanowski, P., Dabrowski, M., Ellert-Miklaszewska, A., Kloss, M., Mieczkowski, J., Maleszewska, M., Ronowicz, A., Piotrowski, A., Komorowski, J., and Kaminska, B.
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- 2012
5. Role of STAT3 in regulation of melanoma cell invasiveness via SERPINA3: P06-151
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Ramji, K., Kulesza, D., Maleszewska, M., Mieczkowski, J., and Kaminska, B.
- Published
- 2012
6. Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis
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Was, H., Krol, S. K., Rotili, D., Mai, A., Wojtas, B., Kaminska, B., and Maleszewska, M.
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Cell Survival ,Histone Deacetylase 2 ,Histone Deacetylase 1 ,Cell proliferation ,Epigenetic drugs ,Glioblastoma ,Glioma stem cells ,HDAC inhibitors ,Histone deacetylase ,Benzamides ,Brain Neoplasms ,Cell Adhesion ,Cell Line, Tumor ,Cell Proliferation ,DNA Methylation ,Drug Screening Assays, Antitumor ,Epigenesis, Genetic ,Glioma ,Histone Deacetylase Inhibitors ,Histone Deacetylases ,Humans ,Neoplastic Stem Cells ,Pyrimidines ,Spheroids, Cellular ,Up-Regulation ,Drug Screening Assays ,Cell Line ,Genetic ,Tumor ,Antitumor ,Cellular ,Spheroids ,Epigenesis - Published
- 2019
7. Endothelial-Mesenchymal Transition: miR-101 as a new target to treat intimal hyperplasia
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Vanchin, B., Maleszewska, M., Kiers, B., Brouwer, L. A., Van Der Pol, B., Pereira, A. C., Harmsen, M. C., Moonen, J. R. A. J., Krenning, G., Restoring Organ Function by Means of Regenerative Medicine (REGENERATE), Vascular Ageing Programme (VAP), Tinbergen group, Cardiovascular Centre (CVC), and Groningen Institute for Organ Transplantation (GIOT)
- Subjects
MAPK7 ,endothelial-mesenchymal transition ,coronary artery stenosis ,macromolecular substances ,miR-101 ,Fluid shear stress (FSS) - Abstract
Introduction: Endothelial-Mesenchymal Transition (EndMT) is a specific form of endothelial dysfunction wherein endothelial cells acquire a mesenchymal phenotype and lose their endothelial functions. We, and others, recently described that EndMT contributes to intimal hyperplasia and atherosclerosis. Pro-fibrotic and inflammatory cytokines, such as IL-1β and TGFβ2 induce EndMT. We found that the mitogen activated protein kinase 7 (MAPK7, also known as Erk5) inhibits EndMT. MAPK7 activation decreases the expression of the histone methyltransferase Enhancer-of-Zeste homologue 2 (Ezh2) thereby maintaining endothelial quiescence.This decrease in Ezh2 expression may therefore be responsible for the protective effects of MAPK7 activation and may thus offer new therapeutic options for the treatment of endothelial dysfunction and intimal hyperplasia. Ezh2 is the catalytic subunit of the Polycomb Repressive Complex 2 that methylates lysine 27 on histone 3 (H3K27me3). H3K27me3 is a repressive chromatin mark that inhibits gene expression. Currently, it is elusive how the crosstalk between MAPK7 and Ezh2 is regulated in the endothelium and if the balance between MAPK7 and EZH2 is disturbed during intimal hyperplasia. Methods and results: We used in silico analysis to identify miRNAs that could evoke posttranscriptional silencing of Ezh2. In Luciferase reporter assays, miR-101 efficiently inhibited expression of the luciferase reporter by interacting with the 3’UTR of EZH2. Using a uniform laminar flow setup, we revealed that MAPK7 induced miR-101 expression, which was blocked by the selective MAPK7 inhibitor BIX02189 (p
- Published
- 2016
8. Histone Modifications in Ageing and Lifespan Regulation
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Maleszewska, M., Mawer, J., and Tessarz, P.
- Published
- 2016
9. Antitumor effect of pharmacological and genetic ablation of selected histone modifying enzymes in human glioma cells
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Król, S.K., primary, Maleszewska, M., additional, Wojtaś, B., additional, and Kamińska, B., additional
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- 2016
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10. Coordinated erasure and adding up epigenetic marks define transcriptional programs during microglia reprogramming
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Kaminska, B., primary, Maleszewska, M., additional, Steranka, A., additional, Smiech, M., additional, Kaza, B., additional, and Dabrowski, M., additional
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- 2016
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11. 241 Tumor-derived Granulocyte-macrophage Colony Stimulating Factor is Responsible for Accumulation of Pro-invasive Microglia/macrophages and Glioma Progression
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Sielska, M., primary, Przanowski, P., additional, Kucharska, J., additional, Gabrusiewicz, K., additional, Kijewska, M., additional, Maleszewska, M., additional, Zawadzka, M., additional, and Kaminska, B., additional
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- 2012
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12. 344 - Coordinated erasure and adding up epigenetic marks define transcriptional programs during microglia reprogramming.
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Kaminska, B., Maleszewska, M., Steranka, A., Smiech, M., Kaza, B., and Dabrowski, M.
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- 2016
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13. 115 - Antitumor effect of pharmacological and genetic ablation of selected histone modifying enzymes in human glioma cells.
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Król, S.K., Maleszewska, M., Wojtaś, B., and Kamińska, B.
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- 2016
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14. Efficient and innocuous delivery of small interfering RNA to microglia using an amphiphilic dendrimer nanovector
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Adria-Jaume Roura, Ling Peng, Marta Maleszewska, Bozena Kaminska, Aleksandra Ellert-Miklaszewska, Sabrina Pricl, Bartłomiej Gielniewski, Yifan Jiang, Natalia Ochocka, Ling Ding, Suzanne Giorgio, Erik Laurini, Nencki Institute of Experimental Biology of the Polish Academy of Sciences, Centre Interdisciplinaire de Nanoscience de Marseille (CINaM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), University of Trieste, Ellert-Miklaszewska, A., Ochocka, N., Maleszewska, M., Ding, L., Laurini, E., Jiang, Y., Roura, A. -J., Giorgio, S., Gielniewski, B., Pricl, S., Peng, L., Kaminska, B., and Università degli studi di Trieste = University of Trieste
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Small interfering RNA ,siRNA delivery ,Dendrimers ,amphiphilic dendrimer ,basal microglial responses ,dendrimer nanovector ,gene silencing ,glioma-initiated response ,inhibitor of differentiation Id1 ,microglial function ,nonviral vector ,primary microglia ,[SDV]Life Sciences [q-bio] ,Cell ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Development ,Transcriptome ,03 medical and health sciences ,Surface-Active Agents ,0302 clinical medicine ,basal microglial response ,Dendrimer ,Amphiphile ,medicine ,Gene silencing ,Animals ,General Materials Science ,RNA, Small Interfering ,Rats, Wistar ,Cells, Cultured ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,Drug Carriers ,Microglia ,Chemistry ,3. Good health ,Cell biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,RNA Interference ,030217 neurology & neurosurgery - Abstract
International audience; Aim: Alterations of microglia, the brain-resident macrophages, are associated with numerous brain pathologies. Genetic manipulation of microglia in diseases using small interfering RNA (siRNA) is hampered by the lack of safe and efficient siRNA delivery methods. We assessed the amphiphilic dendrimer (AD) for functional siRNA delivery and gene knockdown in primary microglia. Materials & methods: We characterized the ability of AD to form nanoparticles with siRNA, and studied their size, surface potential , cell uptake and gene silencing in rodent microglia. Results: AD effectively delivered siRNA to primary microglia and decreased target gene and protein expression, leading to transcriptomic changes without affecting basal microglial functions. Conclusion: The dendrimer AD promises to be an innocuous carrier for siRNA delivery into microglia. Keywords: amphiphilic dendrimer • basal microglial responses • dendrimer nanovector • gene silencing • glioma-initiated response • inhibitor of differentiation Id1 • microglial function • nonviral vector • primary microglia • siRNA delivery Microglia are the resident macrophages of the central nervous system (CNS). They participate in brain development , regulation of homeostasis and synaptic plasticity, as well as protecting the brain from infections, metabolic disturbances or misfolded proteins [1-3]. However, aberrant or chronic microglial activation leads to neuroinflamma-tory brain damage linked to the pathogenesis of stroke and many neurodegenerative and psychiatric disorders [4-9]. Moreover, microglia contribute to the progression of brain tumors, including the most common and deadliest glioblastoma multiforme (GBM) [10]. Microglia and peripheral macrophages massively infiltrate GBM tumors [11], where they become polarized to promote glioma invasion, immunosuppression and angiogenesis [12,13]. Due to their critical role as instigators of inflammatory or pro-tumorigenic events, microglia are considered to be a potentially promising therapeutic target [14]. Therefore, further molecular insights into microglial functions are of paramount importance for our understanding of neurological disorders and for fostering the development of effective treatments for the related diseases. Genetic manipulation using small interfering RNA (siRNA) is frequently used for studying genotype-phenotype relationships and identifying potential drug targets and candidates [15-17]. RNA interference (RNAi) is a biological process in which siRNA molecules specifically inhibit gene translation by neutralizing targeted mRNA molecules via Watson-Crick base-pairing. However, siRNA delivery to microglia has been difficult due to the high immune-reactivity of microglia to transfection agents and the characteristic high charge and enzyme sensitivity of siRNA
- Published
- 2019
15. DMRTA2 supports glioma stem-cell mediated neovascularization in glioblastoma.
- Author
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Maleszewska M, Wojnicki K, Mieczkowski J, Król SK, Jacek K, Śmiech M, Kocyk M, Ciechomska IA, Bujko M, Siedlecki J, Kotulska K, Grajkowska W, Zawadzka M, and Kaminska B
- Subjects
- Adult, Humans, Cell Line, Tumor, Cell Proliferation physiology, Neoplastic Stem Cells metabolism, Transcription Factors metabolism, Brain Neoplasms metabolism, Glioblastoma metabolism, Glioma pathology, Neural Stem Cells metabolism
- Abstract
Glioblastoma (GBM) is the most common and lethal brain tumor in adults. Due to its fast proliferation, diffusive growth and therapy resistance survival times are less than two years for patients with IDH-wildtype GBM. GBM is noted for the considerable cellular heterogeneity, high stemness indices and abundance of the glioma stem-like cells known to support tumor progression, therapeutic resistance and recurrence. Doublesex- and mab-3-related transcription factor a2 (DMRTA2) is involved in maintaining neural progenitor cells (NPC) in the cell cycle and its overexpression suppresses NPC differentiation. Despite the reports showing that primary GBM originates from transformed neural stem/progenitors cells, the role of DMRTA2 in gliomagenesis has not been elucidated so far. Here we show the upregulation of DMRTA2 expression in malignant gliomas. Immunohistochemical staining showed the protein concentrated in small cells with high proliferative potential and cells localized around blood vessels, where it colocalizes with pericyte-specific markers. Knock-down of DMRTA2 in human glioma cells impairs proliferation but not viability of the cells, and affects the formation of the tumor spheres, as evidenced by strong decrease in the number and size of spheres in in vitro cultures. Moreover, the knockdown of DMRTA2 in glioma spheres affects the stabilization of the glioma stem-like cell-dependent tube formation in an in vitro angiogenesis assay. We conclude that DMRTA2 is a new player in gliomagenesis and tumor neovascularization and due to its high expression in malignant gliomas could be a biomarker and potential target for new therapeutic strategies in glioblastoma., (© 2024. The Author(s).)
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- 2024
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16. Targeted sequencing of cancer-related genes reveals a recurrent TOP2A variant which affects DNA binding and coincides with global transcriptional changes in glioblastoma.
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Gielniewski B, Poleszak K, Roura AJ, Szadkowska P, Jacek K, Krol SK, Guzik R, Wiechecka P, Maleszewska M, Kaza B, Marchel A, Czernicki T, Koziarski A, Zielinski G, Styk A, Kawecki M, Szczylik C, Czepko R, Banach M, Kaspera W, Szopa W, Bujko M, Czapski B, Zabek M, Iżycka-Świeszewska E, Kloc W, Nauman P, Cieslewicz J, Grajkowska W, Morosini N, Noushmehr H, Wojtas B, and Kaminska B
- Subjects
- Humans, Prognosis, DNA, Isocitrate Dehydrogenase genetics, Mutation, Glioblastoma pathology, Brain Neoplasms metabolism, Glioma genetics
- Abstract
High-grade gliomas are aggressive, deadly primary brain tumors. Median survival of patients with glioblastoma (GBM, WHO grade 4) is 14 months and <10% of patients survive 2 years. Despite improved surgical strategies and forceful radiotherapy and chemotherapy, the prognosis of GBM patients is poor and did not improve over decades. We performed targeted next-generation sequencing with a custom panel of 664 cancer- and epigenetics-related genes, and searched for somatic and germline variants in 180 gliomas of different WHO grades. Herein, we focus on 135 GBM IDH-wild type samples. In parallel, mRNA sequencing was accomplished to detect transcriptomic abnormalities. We present the genomic alterations in high-grade gliomas and the associated transcriptomic patterns. Computational analyses and biochemical assays showed the influence of TOP2A variants on enzyme activities. In 4/135 IDH-wild type GBMs we found a novel, recurrent mutation in the TOP2A gene encoding topoisomerase 2A (allele frequency [AF] = 0.03, 4/135 samples). Biochemical assays with recombinant, wild type (WT) and variant proteins demonstrated stronger DNA binding and relaxation activity of the variant protein. GBM patients carrying the altered TOP2A had shorter overall survival (median OS 150 vs 500 days, P = .0018). In the GBMs with the TOP2A variant we found transcriptomic alterations consistent with splicing dysregulation. luA novel, recurrent TOP2A mutation, which was found exclusively in four GBMs, results in the TOP2A E948Q variant with altered DNA binding and relaxation activities. The deleterious TOP2A mutation resulting in transcription deregulation in GBMs may contribute to disease pathology., (© 2023 UICC.)
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- 2023
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17. Hypoxia promotes osteogenesis by facilitating acetyl-CoA-mediated mitochondrial-nuclear communication.
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Pouikli A, Maleszewska M, Parekh S, Yang M, Nikopoulou C, Bonfiglio JJ, Mylonas C, Sandoval T, Schumacher AL, Hinze Y, Matic I, Frezza C, and Tessarz P
- Subjects
- Mice, Animals, Acetyl Coenzyme A metabolism, Cell Differentiation physiology, Mitochondria metabolism, Hypoxia metabolism, Oxygen metabolism, Chromatin metabolism, Cells, Cultured, Osteogenesis physiology, Histones metabolism
- Abstract
Bone-derived mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. While hypoxia (low oxygen concentration) was reported to critically support stem cell function and osteogenesis, the molecular events triggering changes in stem cell fate decisions in response to normoxia (high oxygen concentration) remain elusive. Here, we study the impact of normoxia on mitochondrial-nuclear communication during stem cell differentiation. We show that normoxia-cultured murine MSCs undergo profound transcriptional alterations which cause irreversible osteogenesis defects. Mechanistically, high oxygen promotes chromatin compaction and histone hypo-acetylation, particularly on promoters and enhancers of osteogenic genes. Although normoxia induces metabolic rewiring resulting in elevated acetyl-CoA levels, histone hypo-acetylation occurs due to the trapping of acetyl-CoA inside mitochondria owing to decreased citrate carrier (CiC) activity. Restoring the cytosolic acetyl-CoA pool remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is perturbed upon exposure to high oxygen levels and identifies CiC as a novel, oxygen-sensitive regulator of the MSC function., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2022
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18. Chromatin remodeling due to degradation of citrate carrier impairs osteogenesis of aged mesenchymal stem cells.
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Pouikli A, Parekh S, Maleszewska M, Nikopoulou C, Baghdadi M, Tripodi I, Folz-Donahue K, Hinze Y, Mesaros A, Hoey D, Giavalisco P, Dowell R, Partridge L, and Tessarz P
- Subjects
- Osteogenesis genetics, Acetyl Coenzyme A metabolism, Chromatin Assembly and Disassembly, Chromatin metabolism, Histones metabolism, Mesenchymal Stem Cells metabolism
- Abstract
Aging is accompanied by a general decline in the function of many cellular pathways. However, whether these are causally or functionally interconnected remains elusive. Here, we study the effect of mitochondrial-nuclear communication on stem cell aging. We show that aged mesenchymal stem cells exhibit reduced chromatin accessibility and lower histone acetylation, particularly on promoters and enhancers of osteogenic genes. The reduced histone acetylation is due to impaired export of mitochondrial acetyl-CoA, owing to the lower levels of citrate carrier (CiC). We demonstrate that aged cells showed enhanced lysosomal degradation of CiC, which is mediated via mitochondrial-derived vesicles. Strikingly, restoring cytosolic acetyl-CoA levels either by exogenous CiC expression or via acetate supplementation, remodels the chromatin landscape and rescues the osteogenesis defects of aged mesenchymal stem cells. Collectively, our results establish a tight, age-dependent connection between mitochondrial quality control, chromatin and stem cell fate, which are linked together by CiC., (© 2021. The Author(s).)
- Published
- 2021
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19. Identification of the immune gene expression signature associated with recurrence of high-grade gliomas.
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Roura AJ, Gielniewski B, Pilanc P, Szadkowska P, Maleszewska M, Krol SK, Czepko R, Kaspera W, Wojtas B, and Kaminska B
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- Adult, Aged, DNA Copy Number Variations, Dendritic Cells immunology, ErbB Receptors genetics, Female, Humans, Macrophages immunology, Male, Middle Aged, Mutation, PTEN Phosphohydrolase genetics, Trans-Activators genetics, Transcriptome, Tumor Microenvironment genetics, Tumor Microenvironment immunology, Brain Neoplasms genetics, Brain Neoplasms immunology, Glioma genetics, Glioma immunology, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local immunology
- Abstract
High-grade gliomas (HGGs), the most common and aggressive primary brain tumors in adults, inevitably recur due to incomplete surgery or resistance to therapy. Intratumoral genomic and cellular heterogeneity of HGGs contributes to therapeutic resistance, recurrence, and poor clinical outcomes. Transcriptomic profiles of HGGs at recurrence have not been investigated in detail. Using targeted sequencing of cancer-related genes and transcriptomics, we identified single nucleotide variations, small insertions and deletions, copy number aberrations (CNAs), as well as gene expression changes and pathway deregulation in 16 pairs of primary and recurrent HGGs. Most of the somatic mutations identified in primary HGGs were not detected after relapse, suggesting a subclone substitution during the tumor progression. We found a novel frameshift insertion in the ZNF384 gene which may contribute to extracellular matrix remodeling. An inverse correlation of focal CNAs in EGFR and PTEN genes was detected. Transcriptomic analysis revealed downregulation of genes involved in messenger RNA splicing, cell cycle, and DNA repair, while genes related to interferon signaling and phosphatidylinositol (PI) metabolism are upregulated in secondary HGGs when compared to primary HGGs. In silico analysis of the tumor microenvironment identified M2 macrophages and immature dendritic cells as enriched in recurrent HGGs, suggesting a prominent immunosuppressive signature. Accumulation of those cells in recurrent HGGs was validated by immunostaining. Our findings point to a substantial transcriptomic deregulation and a pronounced infiltration of immature dendritic cells in recurrent HGG, which may impact the effectiveness of frontline immunotherapies in the GBM management. KEY MESSAGES: Most of the somatic mutations identified in primary HGGs were not detected after relapse. Focal CNAs in EGFR and PTEN genes are inversely correlated in primary and recurrent HGGs. Transcriptomic changes and distinct immune-related signatures characterize HGG recurrence. Recurrent HGGs are characterized by a prominent infiltration of immature dendritic and M2 macrophages.
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- 2021
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20. Sequential changes in histone modifications shape transcriptional responses underlying microglia polarization by glioma.
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Maleszewska M, Steranka A, Smiech M, Kaza B, Pilanc P, Dabrowski M, and Kaminska B
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- Culture Media, Conditioned pharmacology, Epigenesis, Genetic, Histone Code, Humans, Lipopolysaccharides pharmacology, Tumor Microenvironment, Glioma genetics, Microglia
- Abstract
Microglia, resident myeloid cells of the central nervous system (CNS), act as immune sentinels that contribute to maintenance of physiological homeostasis and respond to any perturbation in CNS. Microglia could be polarized by various stimuli to perform dedicated functions and instigate inflammatory or pro-regenerative responses. Microglia and peripheral macrophages accumulate in glioblastomas (GBMs), malignant brain tumors, but instead of initiating antitumor responses, these cells are polarized to the pro-invasive and immunosuppressive phenotype which persists for a long time and contributes to a "cold" immune microenvironment of GBMs. Molecular mechanisms underlying this long-lasting "microglia memory" are unknown. We hypothesized that this state may rely on epigenetic silencing of inflammation-related genes. In this study, we show that cultured microglia pre-exposed to glioma-conditioned medium (GCM) acquire a "transcriptional memory" and display reduced expression of inflammatory genes after re-stimulation with lipopolysaccharide. Unstimulated microglia have unmethylated DNA and active histone marks at selected gene promoters indicating chromatin accessibility. Adding GCM increases expression and enzymatic activity of histone deacetylases (Hdac), leading to erasure of histone acetylation at tested genes. Later inflammatory genes acquire repressive histone marks (H3K27 trimethylation), which correlates with silencing of their expression. GCM induced genes acquire active histone marks. Hdac inhibitors block GCM-induced changes of histone modifications and restore microglia ability to initiate effective inflammatory responses. Altogether, we show a scenario of distinct histone modifications underlying polarization of microglia by glioma. We demonstrate contribution of epigenetic mechanisms to glioma-induced "transcriptional memory" in microglia resulting in the tumor-supportive phenotype., (© 2020 Wiley Periodicals LLC.)
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- 2021
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21. Histone Modifying Enzymes and Chromatin Modifiers in Glioma Pathobiology and Therapy Responses.
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Ciechomska IA, Jayaprakash C, Maleszewska M, and Kaminska B
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- Brain Neoplasms enzymology, Brain Neoplasms genetics, Chromatin genetics, Chromatin Assembly and Disassembly drug effects, Epigenesis, Genetic drug effects, Glioma enzymology, Glioma genetics, Histone Code drug effects, Histones chemistry, Humans, Brain Neoplasms drug therapy, Brain Neoplasms pathology, Chromatin metabolism, Glioma drug therapy, Glioma pathology, Histones metabolism
- Abstract
Signal transduction pathways directly communicate and transform chromatin to change the epigenetic landscape and regulate gene expression. Chromatin acts as a dynamic platform of signal integration and storage. Histone modifications and alteration of chromatin structure play the main role in chromatin-based gene expression regulation. Alterations in genes coding for histone modifying enzymes and chromatin modifiers result in malfunction of proteins that regulate chromatin modification and remodeling. Such dysregulations culminate in profound changes in chromatin structure and distorted patterns of gene expression. Gliomagenesis is a multistep process, involving both genetic and epigenetic alterations. Recent applications of next generation sequencing have revealed that many chromatin regulation-related genes, including ATRX, ARID1A, SMARCA4, SMARCA2, SMARCC2, BAF155 and hSNF5 are mutated in gliomas. In this review we summarize newly identified mechanisms affecting expression or functions of selected histone modifying enzymes and chromatin modifiers in gliomas. We focus on selected examples of pathogenic mechanisms involving ATRX, histone methyltransferase G9a, histone acetylases/deacetylases and chromatin remodeling complexes SMARCA2/4. We discuss the impact of selected epigenetics alterations on glioma pathobiology, signaling and therapeutic responses. We assess the attempts of targeting defective pathways with new inhibitors.
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- 2020
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22. Search for novel STAT3-dependent genes reveals SERPINA3 as a new STAT3 target that regulates invasion of human melanoma cells.
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Kulesza DW, Ramji K, Maleszewska M, Mieczkowski J, Dabrowski M, Chouaib S, and Kaminska B
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- Binding Sites genetics, Cell Line, Tumor, Cell Movement genetics, Cell Proliferation genetics, Cell Survival genetics, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Gene Regulatory Networks, Humans, Melanoma metabolism, Neoplasm Invasiveness genetics, Neoplasm Invasiveness pathology, Phosphorylation, Promoter Regions, Genetic, STAT3 Transcription Factor antagonists & inhibitors, STAT3 Transcription Factor metabolism, Signal Transduction, Melanoma genetics, Melanoma pathology, STAT3 Transcription Factor genetics, Serpins genetics
- Abstract
Transcription factor signal transducer and activator of transcription 3 (STAT3) is constitutively activated in many cancers and promotes uncontrolled tumor growth and progression through multiple mechanisms. Compelling evidence shows tissue and cell-specific sets of STAT3 targets. Transcriptional targets of STAT3 in melanoma cells are largely unknown. Malignant melanoma is a deadly disease with highly aggressive and drug-resistant behavior. Less than 10% of patients with advanced melanomas reach the 5-year survival, partly due to the aggressive character of the tumor and ineffectiveness of current therapeutics for treating metastatic melanoma. STAT3 is constitutively activated in melanoma cells and plays important roles in its growth and angiogenesis in tumor xenograft studies. Moreover, highly metastatic melanoma cells have higher levels of active STAT3 than poorly metastatic ones. To identify genes that are driven by STAT3 in human melanoma cells, we performed JAK/STAT signaling specific and global gene expression profiling of human melanoma cells with silenced STAT3 expression. For selected genes, we performed computational identification of putative STAT3-binding sites and validated direct interactions STAT3 with defined promoters by using chromatin immunoprecipitation followed by qPCR. We found that STAT3 knockdown does not affect human melanoma cell viability, proliferation, or response to chemotherapeutics. We show that STAT3 regulates a discrete set of genes in melanoma cells, including SERPINA3, a novel STAT3 target gene, which is functionally involved in regulation of melanoma migration and invasion. Knockdown of STAT3 impaired cell migration and invasion, in part via regulation of its transcriptional target SERPINA3. Our results present novel targets and functions of STAT3 in melanoma cells.
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- 2019
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23. Efficient and innocuous delivery of small interfering RNA to microglia using an amphiphilic dendrimer nanovector.
- Author
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Ellert-Miklaszewska A, Ochocka N, Maleszewska M, Ding L, Laurini E, Jiang Y, Roura AJ, Giorgio S, Gielniewski B, Pricl S, Peng L, and Kaminska B
- Subjects
- Animals, Cells, Cultured, Mice, Inbred C57BL, Microglia cytology, Microglia metabolism, RNA, Small Interfering genetics, Rats, Wistar, Dendrimers chemistry, Drug Carriers chemistry, RNA Interference, RNA, Small Interfering administration & dosage, Surface-Active Agents chemistry
- Abstract
Aim: Alterations of microglia, the brain-resident macrophages, are associated with numerous brain pathologies. Genetic manipulation of microglia in diseases using small interfering RNA (siRNA) is hampered by the lack of safe and efficient siRNA delivery methods. We assessed the amphiphilic dendrimer (AD) for functional siRNA delivery and gene knockdown in primary microglia. Materials & methods: We characterized the ability of AD to form nanoparticles with siRNA, and studied their size, surface potential, cell uptake and gene silencing in rodent microglia. Results: AD effectively delivered siRNA to primary microglia and decreased target gene and protein expression, leading to transcriptomic changes without affecting basal microglial functions. Conclusion: The dendrimer AD promises to be an innocuous carrier for siRNA delivery into microglia.
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- 2019
- Full Text
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24. Gliosarcoma Is Driven by Alterations in PI3K/Akt, RAS/MAPK Pathways and Characterized by Collagen Gene Expression Signature.
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Wojtas B, Gielniewski B, Wojnicki K, Maleszewska M, Mondal SS, Nauman P, Grajkowska W, Glass R, Schüller U, Herold-Mende C, and Kaminska B
- Abstract
Gliosarcoma is a very rare brain tumor reported to be a variant of glioblastoma (GBM), IDH-wildtype. While differences in molecular and histological features between gliosarcoma and GBM were reported, detailed information on the genetic background of this tumor is lacking. We intend to fill in this knowledge gap by the complex analysis of somatic mutations, indels, copy number variations, translocations and gene expression patterns in gliosarcomas. Using next generation sequencing, we determined somatic mutations, copy number variations (CNVs) and translocations in 10 gliosarcomas. Six tumors have been further subjected to RNA sequencing analysis and gene expression patterns have been compared to those of GBMs. We demonstrate that gliosarcoma bears somatic alterations in gene coding for PI3K/Akt ( PTEN , PI3K ) and RAS/MAPK ( NF1 , BRAF ) signaling pathways that are crucial for tumor growth. Interestingly, the frequency of PTEN alterations in gliosarcomas was much higher than in GBMs. Aberrations of PTEN were the most frequent and occurred in 70% of samples. We identified genes differentially expressed in gliosarcoma compared to GBM (including collagen signature) and confirmed a difference in the protein level by immunohistochemistry. We found several novel translocations (including translocations in the RABGEF1 gene) creating potentially unfavorable combinations. Collected results on genetic alterations and transcriptomic profiles offer new insights into gliosarcoma pathobiology, highlight differences in gliosarcoma and GBM genetic backgrounds and point out to distinct molecular cues for targeted treatment.
- Published
- 2019
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25. Histone deacetylase inhibitors exert anti-tumor effects on human adherent and stem-like glioma cells.
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Was H, Krol SK, Rotili D, Mai A, Wojtas B, Kaminska B, and Maleszewska M
- Subjects
- Benzamides pharmacology, Brain Neoplasms drug therapy, Cell Adhesion, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Drug Screening Assays, Antitumor, Epigenesis, Genetic drug effects, Glioma drug therapy, Histone Deacetylase 1 genetics, Histone Deacetylase 2 genetics, Histone Deacetylases genetics, Humans, Neoplastic Stem Cells drug effects, Pyrimidines pharmacology, Spheroids, Cellular drug effects, Up-Regulation drug effects, Brain Neoplasms genetics, DNA Methylation drug effects, Glioma genetics, Histone Deacetylase Inhibitors pharmacology, Neoplastic Stem Cells cytology, Spheroids, Cellular cytology
- Abstract
Background: The diagnosis of glioblastoma (GBM), a most aggressive primary brain tumor with a median survival of 14.6 months, carries a dismal prognosis. GBMs are characterized by numerous genetic and epigenetic alterations, affecting patient survival and treatment response. Epigenetic mechanisms are deregulated in GBM as a result of aberrant expression/activity of epigenetic enzymes, including histone deacetylases (HDAC) which remove acetyl groups from histones regulating chromatin accessibility. Nevertheless, the impact of class/isoform-selective HDAC inhibitors (HDACi) on glioma cells, including glioma stem cells, had not been systematically determined., Results: Comprehensive analysis of the public TCGA dataset revealed the increased expression of HDAC 1, 2, 3, and 7 in malignant gliomas. Knockdown of HDAC 1 and 2 in human GBM cells significantly decreased cell proliferation. We tested the activity of 2 new and 3 previously described HDACi with different class/isoform selectivity on human GBM cells. All tested compounds exerted antiproliferative properties on glioma cells. However, the HDACi 1 and 4 blocked proliferation of glioblastoma cells leading to G2/M growth arrest without affecting astrocyte survival. Moreover, 1 and 4 at low micromolar concentrations displayed cytotoxic and antiproliferative effects on sphere cultures enriched in glioma stem cells., Conclusions: We identified two selective HDAC inhibitors that blocked proliferation of glioblastoma cells, but did not affect astrocyte survival. These new and highly effective inhibitors should be considered as promising candidates for further investigation in preclinical GBM models.
- Published
- 2019
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26. Deregulation of epigenetic mechanisms in cancer.
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Maleszewska M, Wojtas B, and Kamińska B
- Subjects
- DNA Methylation, Histones chemistry, Histones metabolism, Humans, Proteomics, Epigenesis, Genetic, Gene Expression Regulation, Neoplastic, Neoplasms genetics
- Abstract
Gene expression of both normal and cancer cell is tightly regulated by specific transcription regulators and epigenetic mechanisms such as DNA methylation, histone modifications (acetylation, methylation, phosphorylation), nucleosome remodeling and non-coding RNAs. Deregulation of epigenetic mechanisms plays a pivotal role in cancer, although researchers debate if it is a cause or a consequence of oncogenic transformation. Independently from the way in which epigenetic alterations arise in cancer, downstream effects will result in profound changes in transcriptomic and subsequently proteomic profiles. In most cases, changes in expression of epigenetic genes produce functional advantages in cell proliferation, tumor growth and/or migration capacity. Most of epigenetic changes in cancer are triggered by genomic alterations in specific genes that are involved in controlling one of the epigenetic mechanisms. However, there are also mutations in cell metabolism-related genes that affect activities of DNA demethylating enzymes and histone modifiers. Histone modifications are deregulated in cancer mostly due to alterations in genes coding for enzymes that attach or remove histone modifications. Mutations in genes coding for nucleosome remodelers result in aberrant global chromatin organization and facilitate subsequent global alterations of gene copy number or translocations. Recent advancements in next generation sequencing allowed for more precise mapping of global changes in the epigenetic landscape in cancer.
- Published
- 2018
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27. The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence.
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Maleszewska M, Vanchin B, Harmsen MC, and Krenning G
- Subjects
- Cell Adhesion genetics, Cell Cycle genetics, Cell Proliferation, Down-Regulation genetics, Enhancer of Zeste Homolog 2 Protein, Enzyme Activation, Gene Ontology, Gene Regulatory Networks, Human Umbilical Vein Endothelial Cells cytology, Humans, Mitogen-Activated Protein Kinase 7 metabolism, Models, Biological, Polycomb Repressive Complex 2 genetics, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells enzymology, Polycomb Repressive Complex 2 metabolism, Rheology, Stress, Mechanical
- Abstract
High uniform fluid shear stress (FSS) is atheroprotective and preserves the endothelial phenotype and function through activation of downstream mediators such as MAPK7 (Erk5). Endothelial cells respond to FSS thanks to mechanotransduction. However, how the resulting signaling is integrated and resolved at the epigenetic level remains elusive. We hypothesized that Polycomb methyltransferase EZH2 is involved in the effects of FSS in human endothelial cells. We showed that FSS decreases the expression of the Polycomb methyltransferase EZH2. Despite simultaneous activation of MAPK7, MAPK7 pathway does not directly influence the transcription of EZH2. Interestingly though, the knockdown of EZH2 activates the protective MAPK7 signaling in endothelial cells, even in the absence of FSS. To understand the influence of the FSS-decreased expression of EZH2 on endothelial transcriptome, we performed RNA-seq and differential gene expression analysis. We identified candidate groups of genes dependent on both EZH2 and FSS. Among those, Gene Ontology overrepresentation analysis revealed highly significant enrichment of the cell cycle-related genes, suggesting changes in proliferation. Indeed, the depletion of EZH2 strongly inhibited endothelial proliferation, indicating cell cycle arrest. The concomitant decrease in CCNA expression suggests the transition of endothelial cells into a quiescent phenotype. Further bioinformatical analysis suggested TXNIP as a possible mediator between EZH2 and cell cycle-related gene network. Our data show that EZH2 is a FSS-responsive gene. Decreased EZH2 levels enhance the activation of the atheroprotective MAPK7 signaling. Decrease in EZH2 under FSS mediates the decrease in the expression of the network of cell cycle-related genes, which allows the cells to enter quiescence. EZH2 is therefore important for the protective effects of FSS in endothelium.
- Published
- 2016
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28. Nrf2-heme oxygenase-1 axis in mucoepidermoid carcinoma of the lung: Antitumoral effects associated with down-regulation of matrix metalloproteinases.
- Author
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Tertil M, Golda S, Skrzypek K, Florczyk U, Weglarczyk K, Kotlinowski J, Maleszewska M, Czauderna S, Pichon C, Kieda C, Jozkowicz A, and Dulak J
- Subjects
- Animals, Apoptosis, Blotting, Western, Carcinoma, Mucoepidermoid metabolism, Carcinoma, Mucoepidermoid pathology, Carcinoma, Non-Small-Cell Lung metabolism, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung prevention & control, Cell Proliferation, Down-Regulation, Fluorescent Antibody Technique, Gene Expression Profiling, Heme Oxygenase-1 genetics, Humans, Immunoenzyme Techniques, Lung Neoplasms metabolism, Lung Neoplasms pathology, Male, Matrix Metalloproteinases genetics, Mice, Mice, Inbred NOD, Mice, SCID, NF-E2-Related Factor 2 genetics, Oxidative Stress, RNA, Messenger genetics, Real-Time Polymerase Chain Reaction, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Tumor Cells, Cultured, Tumor Microenvironment, Xenograft Model Antitumor Assays, Carcinoma, Mucoepidermoid prevention & control, Gene Expression Regulation, Neoplastic, Heme Oxygenase-1 metabolism, Lung Neoplasms prevention & control, Matrix Metalloproteinases metabolism, NF-E2-Related Factor 2 metabolism
- Abstract
Lung mucoepidermoid carcinoma (MEC) is a very poorly characterized rare subtype of non-small-cell lung cancer (NSCLC) associated with more favorable prognoses than other forms of intrathoracic malignancies. We have previously identified that heme oxygenase-1 (HO-1, encoded by HMOX1) inhibits MEC tumor growth and modulates the transcriptome of microRNAs. Here we investigate the role of a major upstream regulator of HO-1 and a master regulator of cellular antioxidant responses, transcription factor Nrf2, in MEC biology. Nrf2 overexpression in the NCI-H292 MEC cell line mimicked the phenotype of HO-1 overexpressing cells, leading to inhibition of cell proliferation and migration and down-regulation of oncogenic miR-378. HMOX1 silencing identified HO-1 as a major mediator of Nrf2 action. Nrf2- and HO-1 overexpressing cells exhibited strongly diminished expression of multiple matrix metalloproteinases and inflammatory cytokine interleukin-1β, which was confirmed in an NCI-HO-1 xenograft model. Overexpression of HO-1 altered not only human MMP levels in tumor cells but also murine MMP levels within tumor microenvironment and metastatic niche. This could possibly contribute to decreased metastasis to the lungs and inhibitory effects of HO-1 on MEC tumor growth. Our profound transcriptome analysis and molecular characterization of the mucoepidermoid lung carcinoma helps to understand the specific clinical presentations of these tumors, emphasizing a unique antitumoral role of the Nrf2-HO-1 axis., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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29. Endothelial-to-mesenchymal transition contributes to fibro-proliferative vascular disease and is modulated by fluid shear stress.
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Moonen JR, Lee ES, Schmidt M, Maleszewska M, Koerts JA, Brouwer LA, van Kooten TG, van Luyn MJ, Zeebregts CJ, Krenning G, and Harmsen MC
- Subjects
- Animals, Aorta, Thoracic metabolism, Aorta, Thoracic pathology, Aorta, Thoracic physiopathology, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases physiopathology, Carotid Arteries metabolism, Carotid Arteries physiopathology, Carotid Artery Diseases genetics, Carotid Artery Diseases metabolism, Carotid Artery Diseases physiopathology, Disease Models, Animal, Endothelial Cells metabolism, Fibrosis, HEK293 Cells, Human Umbilical Vein Endothelial Cells metabolism, Human Umbilical Vein Endothelial Cells pathology, Humans, MAP Kinase Kinase 5 genetics, MAP Kinase Kinase 5 metabolism, Male, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 7 genetics, Mitogen-Activated Protein Kinase 7 metabolism, Neointima, RNA Interference, Regional Blood Flow, Stress, Mechanical, Swine, Time Factors, Transfection, Aortic Diseases pathology, Carotid Arteries pathology, Carotid Artery Diseases pathology, Cell Proliferation, Endothelial Cells pathology, Epithelial-Mesenchymal Transition, Mechanotransduction, Cellular, Plaque, Atherosclerotic, Vascular Remodeling
- Abstract
Aims: Neointimal hyperplasia is a common feature of fibro-proliferative vascular disease and characterizes initial stages of atherosclerosis. Neointimal lesions mainly comprise smooth muscle-like cells. The presence of these lesions is related to local differences in shear stress. Neointimal cells may arise through migration and proliferation of smooth muscle cells from the media. However, a role for the endothelium as a source of smooth muscle-like cells has largely been disregarded. Here, we investigated the role of endothelial-to-mesenchymal transition (EndMT) in neointimal hyperplasia and atherogenesis, and studied its modulation by shear stress., Methods and Results: In human atherosclerotic plaques and porcine aortic tissues, myo-endothelial cells were identified, suggestive for EndMT. Flow disturbance by thoracic-aortic constriction in mice similarly showed the presence of myo-endothelial cells specifically in regions exposed to disturbed flow. While uniform laminar shear stress (LSS) was found to inhibit EndMT, endothelial cells exposed to disturbed flow underwent EndMT, in vitro and in vivo, and showed atherogenic differentiation. Gain- and loss-of-function studies using a constitutive active mutant of MEK5 and short hairpins targeting ERK5 established a pivotal role for ERK5 signalling in the inhibition of EndMT., Conclusion: Together, these data suggest that EndMT contributes to neointimal hyperplasia and induces atherogenic differentiation of endothelial cells. Importantly, we uncovered that EndMT is modulated by shear stress in an ERK5-dependent manner. These findings provide new insights in the role of adverse endothelial plasticity in vascular disease and identify a novel atheroprotective mechanism of uniform LSS, namely inhibition of EndMT., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)
- Published
- 2015
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30. Down-regulation of IKKβ expression in glioma-infiltrating microglia/macrophages is associated with defective inflammatory/immune gene responses in glioblastoma.
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Mieczkowski J, Kocyk M, Nauman P, Gabrusiewicz K, Sielska M, Przanowski P, Maleszewska M, Rajan WD, Pszczolkowska D, Tykocki T, Grajkowska W, Kotulska K, Roszkowski M, Kostkiewicz B, and Kaminska B
- Subjects
- Animals, Brain Neoplasms enzymology, Brain Neoplasms genetics, Brain Neoplasms immunology, Down-Regulation, Gene Expression Profiling, Glioblastoma enzymology, Glioblastoma genetics, Glioblastoma immunology, Humans, I-kappa B Kinase genetics, Macrophages enzymology, Macrophages immunology, Macrophages metabolism, Male, Microglia enzymology, Microglia immunology, Microglia metabolism, Rats, Rats, Wistar, Brain Neoplasms pathology, Glioblastoma pathology, I-kappa B Kinase metabolism, Macrophages pathology, Microglia pathology
- Abstract
Glioblastoma (GBM) is an aggressive malignancy associated with profound host immunosuppression. Microglia and macrophages infiltrating GBM acquire the pro-tumorigenic, M2 phenotype and support tumor invasion, proliferation, survival, angiogenesis and block immune responses both locally and systematically. Mechanisms responsible for immunological deficits in GBM patients are poorly understood. We analyzed immune/inflammatory gene expression in five datasets of low and high grade gliomas, and performed Gene Ontology and signaling pathway analyses to identify defective transcriptional responses. The expression of many immune/inflammatory response and TLR signaling pathway genes was reduced in high grade gliomas compared to low grade gliomas. In particular, we found the reduced expression of the IKBKB, a gene coding for IKKβ, which phosphorylates IκB proteins and represents a convergence point for most signal transduction pathways leading to NFκB activation. The reduced IKBKB expression and IKKβ levels in GBM tissues were demonstrated by qPCR, Western blotting and immunohistochemistry. The IKKβ expression was down-regulated in microglia/macrophages infiltrating glioblastoma. NFκB activation, prominent in microglia/macrophages infiltrating low grade gliomas, was reduced in microglia/macrophages in glioblastoma tissues. Down-regulation of IKBKB expression and NFκB signaling in microglia/macrophages infiltrating glioblastoma correlates with defective expression of immune/inflammatory genes and M2 polarization that may result in the global impairment of anti-tumor immune responses in glioblastoma.
- Published
- 2015
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31. Deregulation of histone-modifying enzymes and chromatin structure modifiers contributes to glioma development.
- Author
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Maleszewska M and Kaminska B
- Subjects
- Age Factors, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Epigenesis, Genetic drug effects, Gene Expression Regulation, Enzymologic drug effects, Gene Expression Regulation, Neoplastic drug effects, Glioma drug therapy, Glioma mortality, Glioma pathology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylase Inhibitors therapeutic use, Histones genetics, Humans, Mutation, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Nucleosomes metabolism, Chromatin genetics, Chromatin metabolism, Glioma etiology, Glioma metabolism, Histones metabolism
- Abstract
The epigenetic landscape is deregulated in cancer due to aberrant activation or inactivation of enzymes maintaining and modifying the epigenome. Histone modifications and global aberrations at the histone level may result in distorted patterns of gene expression, and malfunction of proteins that regulate chromatin modification and remodeling. Recent whole genome studies demonstrated that histones and chaperone proteins harbor mutations that may result in gross alterations of the epigenome leading to genome instability. Glioma development is a multistep process, involving genetic and epigenetic alterations. This review summarizes newly identified mechanisms affecting expression/functions of histone-modifying enzymes and chromatin modifiers in gliomas. We discuss recent approaches to overcome epigenetic alterations with histone-modifying enzyme inhibitors and their prospects for glioma therapy.
- Published
- 2015
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32. Enhancer of zeste homolog-2 (EZH2) methyltransferase regulates transgelin/smooth muscle-22α expression in endothelial cells in response to interleukin-1β and transforming growth factor-β2.
- Author
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Maleszewska M, Gjaltema RA, Krenning G, and Harmsen MC
- Subjects
- Cell Line, Transformed, Chromatin Assembly and Disassembly drug effects, DNA Methylation drug effects, Enhancer of Zeste Homolog 2 Protein, Enzyme Inhibitors pharmacology, Epigenesis, Genetic drug effects, Gene Expression Regulation, Histones metabolism, Human Umbilical Vein Endothelial Cells enzymology, Humans, Microfilament Proteins genetics, Muscle Proteins genetics, Polycomb Repressive Complex 2 antagonists & inhibitors, Polycomb Repressive Complex 2 genetics, Promoter Regions, Genetic, RNA Interference, Signal Transduction drug effects, Transfection, Vascular Remodeling, Human Umbilical Vein Endothelial Cells drug effects, Interleukin-1beta pharmacology, Microfilament Proteins metabolism, Muscle Proteins metabolism, Polycomb Repressive Complex 2 metabolism, Transforming Growth Factor beta2 pharmacology
- Abstract
Smooth muscle-22α (SM22α), encoded by transgelin (TAGLN), is expressed in mesenchymal lineage cells, including myofibroblasts and smooth muscle cells. It is an F-actin binding protein that regulates the organization of actin cytoskeleton, cellular contractility and motility. SM22α is crucial for the maintenance of smooth muscle cell phenotype and its function. SM22α is also expressed in the processes of mesenchymal transition of epithelial (EMT) or endothelial cells (EndMT). The expression of TAGLN/SM22α is induced by transforming growth factor-β (TGFβ) signaling and enhanced by concomitant interleukin-1β (IL-1β) signaling. We investigated the epigenetic regulation of TAGLN expression by enhancer of zeste homolog-2 (EZH2), the methyltransferase of Polycomb, in the context of TGFβ and IL-1β signaling in endothelial cells. We demonstrate that the expression of EZH2 in endothelial cells was regulated by the inflammatory cytokine IL-1β. A decrease in both expression and activity of EZH2 led to an increase in TAGLN expression. Inhibition of EZH2 augmented TGFβ2-induced SM22α expression. The decrease of EZH2 levels in endothelial cells co-stimulated with IL-1β and TGFβ2 correlated with decreased H3K27me3 levels at the TAGLN proximal promoter. Moreover, the SM22α expression increased. Taken together, this suggests that EZH2 regulates the chromatin structure at the TAGLN promoter through tri-methylation of H3K27. EZH2 therefore acts as an epigenetic integrator of IL-1β and TGFβ2 signaling, providing an example of how cellular signaling can be resolved at the level of epigenetic regulation. Since IL-1β and TGFβ2 represent the pro-inflammatory and pro-fibrotic conditions during vascular fibroproliferative disease, we surmise that EZH2, as the molecule that integrates their signaling, could also be a promising target for development of future therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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33. Nrf2 regulates angiogenesis: effect on endothelial cells, bone marrow-derived proangiogenic cells and hind limb ischemia.
- Author
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Florczyk U, Jazwa A, Maleszewska M, Mendel M, Szade K, Kozakowska M, Grochot-Przeczek A, Viscardi M, Czauderna S, Bukowska-Strakova K, Kotlinowski J, Jozkowicz A, Loboda A, and Dulak J
- Subjects
- Active Transport, Cell Nucleus, Animals, Antioxidants metabolism, Aorta pathology, Cells, Cultured, Endothelium, Vascular pathology, Female, Femoral Artery pathology, Gene Expression, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Humans, Ischemia physiopathology, Male, Membrane Proteins genetics, Membrane Proteins metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Muscle, Skeletal metabolism, NF-E2-Related Factor 2 genetics, Oxidative Stress, Stem Cells physiology, Transcriptome, Bone Marrow Cells physiology, Endothelial Cells physiology, Hindlimb blood supply, NF-E2-Related Factor 2 metabolism, Neovascularization, Physiologic
- Abstract
Aims: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, interleukin-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PACs). Here we investigated angiogenic properties of Nrf2 in PACs, endothelial cells, and inflammation-related revascularization., Results: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration, and angiogenic potential of murine PACs and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2(-/-) in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2(-/-) mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, the anti-inflammatory agent etodolac tended to diminish blood flow in the Nrf2(-/-) mice., Innovation: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PACs., Conclusion: Nrf2 contributes to angiogenic potential of both endothelial cells and PACs; however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PACs in such conditions.
- Published
- 2014
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34. The effects of selected inhibitors of histone modifying enzyme on C6 glioma cells.
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Maleszewska M, Steranka A, and Kaminska B
- Subjects
- Acetylation, Adenosine analogs & derivatives, Adenosine pharmacology, Animals, Azepines pharmacology, Brain Neoplasms pathology, Cell Line, Tumor, Cell Survival drug effects, Epigenesis, Genetic, Glioma pathology, Hydroxamic Acids pharmacology, Piperazines pharmacology, Quinazolines pharmacology, Rats, Valproic Acid pharmacology, Brain Neoplasms enzymology, Enzyme Inhibitors pharmacology, Glioma enzymology, Histones metabolism
- Abstract
Background: Aberrant epigenetic histone modifications are implicated in cancer pathobiology, therefore histone modifying enzymes are emerging targets for anti-cancer therapy. There is a few evidence for deregulation of the histone modifying enzymes in glioblastomas. Glioma treatment is a clinical challenge due to its resistance to current therapies., Methods: The effect of selected inhibitors on epigenetic modifications and viability of glioma C6 cells were studied using immunofluorescence and MTT metabolism test., Results: We found that VPA and TSA increase histone H4 acetylation in glioma cells, while chaetocin and BIX01294 at low concentrations reduce H3K9me3, and 3DZNep decreases H3K27me3. Long-term treatment with some epigenetic inhibitors affects viability of glioma cells., Conclusions: We established the concentrations of selected inhibitors which in C6 glioma cells inhibit the enzyme activity, but do not decrease cell viability, hence allow to study the role of histone modifications in C6 glioma biology., (Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.)
- Published
- 2014
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35. Is glioblastoma an epigenetic malignancy?
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Maleszewska M and Kaminska B
- Abstract
Epigenetic modifications control gene expression by regulating the access of nuclear proteins to their target DNA and have been implicated in both normal cell differentiation and oncogenic transformation. Epigenetic abnormalities can occur both as a cause and as a consequence of cancer. Oncogenic transformation can deeply alter the epigenetic information enclosed in the pattern of DNA methylation or histone modifications. In addition, in some cancers epigenetic dysfunctions can drive oncogenic transformation. Growing evidence emphasizes the interplay between metabolic disturbances, epigenomic changes and cancer, i.e., mutations in the metabolic enzymes SDH, FH, and IDH may contribute to cancer development. Epigenetic-based mechanisms are reversible and the possibility of "resetting" the abnormal cancer epigenome by applying pharmacological or genetic strategies is an attractive, novel approach. Gliomas are incurable with all current therapeutic approaches and new strategies are urgently needed. Increasing evidence suggests the role of epigenetic events in development and/or progression of gliomas. In this review, we summarize current data on the occurrence and significance of mutations in the epigenetic and metabolic enzymes in pathobiology of gliomas. We discuss emerging therapies targeting specific epigenetic modifications or chromatin modifying enzymes either alone or in combination with other treatment regimens.
- Published
- 2013
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36. Distinct roles of CSF family cytokines in macrophage infiltration and activation in glioma progression and injury response.
- Author
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Sielska M, Przanowski P, Wylot B, Gabrusiewicz K, Maleszewska M, Kijewska M, Zawadzka M, Kucharska J, Vinnakota K, Kettenmann H, Kotulska K, Grajkowska W, and Kaminska B
- Subjects
- Animals, Astrocytes metabolism, Astrocytes pathology, Brain Neoplasms genetics, Brain Neoplasms immunology, Cell Line, Tumor, Disease Progression, Female, Gene Knockdown Techniques, Glioma genetics, Glioma immunology, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Humans, Macrophage Activation, Macrophage Colony-Stimulating Factor genetics, Macrophages metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microglia metabolism, Microglia pathology, Mutation, Neoplasm Invasiveness, Phenotype, RNA, Neoplasm genetics, Brain Neoplasms pathology, Gene Expression Regulation, Neoplastic, Glioma pathology, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Macrophage Colony-Stimulating Factor metabolism, Macrophages pathology
- Abstract
Gliomas attract brain-resident (microglia) and peripheral macrophages and reprogram these cells into immunosuppressive, pro-invasive cells. M-CSF (macrophage colony-stimulating factor, encoded by the CSF1 gene) has been implicated in the control of recruitment and polarization of macrophages in several cancers. We found that murine GL261 glioma cells overexpress GM-CSF (granulocyte-macrophage colony-stimulating factor encoded by the CSF2 gene) but not M-CSF when compared to normal astrocytes. Knockdown of GM-CSF in GL261 glioma cells strongly reduced microglia-dependent invasion in organotypical brain slices and growth of intracranial gliomas and extended animal survival. The number of infiltrating microglia/macrophages (Iba1(+) cells) and intratumoural angiogenesis were reduced in murine gliomas depleted of GM-CSF. M1/M2 gene profiling in sorted microglia/macrophages suggests impairment of their pro-invasive activation in GM-CSF-depleted gliomas. Deficiency of M-CSF (op/op mice) did not affect glioma growth in vivo and the accumulation of Iba1(+) cells, but impaired accumulation of Iba1(+) cells in response to demyelination. These results suggest that distinct cytokines of the CSF family contribute to macrophage infiltration of tumours and in response to injury. The expression of CSF2 (but not CSF1) was highly up-regulated in glioblastoma patients and we found an inverse correlation between CSF2 expression and patient survival. Therefore we propose that GM-CSF triggers and drives the alternative activation of tumour-infiltrating microglia/macrophages in which these cells support tumour growth and angiogenesis and shape the immune microenvironment of gliomas., (Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)
- Published
- 2013
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37. Molecular definition of the pro-tumorigenic phenotype of glioma-activated microglia.
- Author
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Ellert-Miklaszewska A, Dabrowski M, Lipko M, Sliwa M, Maleszewska M, and Kaminska B
- Subjects
- Animals, Animals, Newborn, Carcinogenesis drug effects, Cell Movement drug effects, Cell Proliferation, Cerebral Cortex cytology, Culture Media, Conditioned pharmacology, Cytokines metabolism, Enzyme Inhibitors pharmacology, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Gene Expression Regulation, Neoplastic genetics, Lipopolysaccharides pharmacology, Oligonucleotide Array Sequence Analysis, Phagocytosis drug effects, Protein Serine-Threonine Kinases metabolism, Rats, Rats, Wistar, Signal Transduction drug effects, Transforming Growth Factor beta1 metabolism, NF-kappaB-Inducing Kinase, Carcinogenesis genetics, Cell Movement physiology, Glioma pathology, Microglia physiology, Signal Transduction physiology
- Abstract
Microglia are myeloid cells residing in the central nervous system that participate in inflammatory responses and could promote injury and repair. Gliomas attract microglia and polarize them into tumor-supporting cells that participate in matrix remodeling, invasion, angiogenesis, and suppression of adaptive immunity. Although signaling pathways and critical regulators underlying classical inflammation are well established, signal transduction and transcriptional circuits underlying the alternative activation of microglia are poorly known. Using primary rat microglial cultures exposed to glioma conditioned medium or lipopolysaccharide (LPS), we demonstrate that microglia adapt different fates and polarize into pro-inflammatory or alternatively activated cells. Glioma-derived factors increased cell motility, phagocytosis, and sustained proliferation of microglial cells that was mediated by enhanced focal adhesion kinase and PI-3K/Akt signaling. The signals from glioma cells induced ERK and p38 MAPK but not JNK signaling and failed to activate pro-inflammatory Stat1 and NFκB signaling in microglial cells. Transcriptome analysis of microglial cultures at 6 h after exposure to glioma-conditioned medium or LPS revealed different patterns of gene expression. Glioma-induced activation was associated with induction of genes coding for ID (inhibitor of DNA binding) 1/3 and c-Myc, markers of the alternative phenotype Arg1, MT1-MMP, CXCL14, and numerous cytokines/chemokines implicated in immune cell trafficking. Many classical inflammation-related genes and signaling pathways failed to be induced. Our study indicates for the first time molecular pathways that direct microglia toward the pro-invasive, immunosuppressive phenotype., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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38. IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner.
- Author
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Maleszewska M, Moonen JR, Huijkman N, van de Sluis B, Krenning G, and Harmsen MC
- Subjects
- Active Transport, Cell Nucleus immunology, Animals, Cellular Microenvironment drug effects, Endothelial Cells pathology, Epithelial-Mesenchymal Transition drug effects, Fibrosis immunology, Fibrosis pathology, Human Umbilical Vein Endothelial Cells, Humans, Inflammation immunology, Inflammation pathology, Interleukin-1beta pharmacology, Male, Mice, Transforming Growth Factor beta1 immunology, Transforming Growth Factor beta1 pharmacology, Transforming Growth Factor beta2 pharmacology, Cell Nucleus immunology, Cellular Microenvironment immunology, Endothelial Cells immunology, Epithelial-Mesenchymal Transition immunology, Interleukin-1beta immunology, NF-kappa B immunology, Transforming Growth Factor beta2 immunology
- Abstract
Endothelial to mesenchymal transition (EndMT) contributes to fibrotic diseases. The main inducer of EndMT is TGFβ signaling. TGFβ2 is the dominant isoform in the physiological embryonic EndMT, but its role in the pathological EndMT in the context of inflammatory co-stimulation is not known. The aim of this study was to investigate TGFβ2-induced EndMT in the context of inflammatory IL-1β signaling. Co-stimulation with IL-1β and TGFβ2, but not TGFβ1, caused synergistic induction of EndMT. Also, TGFβ2 was the only TGFβ isoform that was progressively upregulated during EndMT. External IL-1β stimulation was dispensable once EndMT was induced. The inflammatory transcription factor NFκB was upregulated in an additive manner by IL-1β and TGFβ2 co-stimulation. Co-stimulation also led to the nuclear translocation of NFκB which was sustained over long-term treatment. Activation of NFκB was indispensable for the co-induction of EndMT. Our data suggest that the microenvironment at the verge between inflammation (IL-1β) and tissue remodeling (TGFβ2) can strongly promote the process of EndMT. Therefore our findings provide new insights into the mechanisms of pathological EndMT., (Copyright © 2012 Elsevier GmbH. All rights reserved.)
- Published
- 2013
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39. Chromatin modifications in hematopoietic multipotent and committed progenitors are independent of gene subnuclear positioning relative to repressive compartments.
- Author
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Guillemin C, Maleszewska M, Guais A, Maës J, Rouyez MC, Yacia A, Fichelson S, Goodhardt M, and Francastel C
- Subjects
- Acetylation, Animals, Cell Differentiation genetics, Cell Lineage, Erythroid Cells metabolism, Globins metabolism, Hematopoiesis genetics, Hematopoietic Stem Cells cytology, Histones metabolism, Humans, Immunoglobulin kappa-Chains genetics, Infant, Mice, Multipotent Stem Cells cytology, Cell Compartmentation, Chromatin metabolism, Gene Order, Hematopoietic Stem Cells metabolism, Multipotent Stem Cells metabolism
- Abstract
To further clarify the contribution of nuclear architecture in the regulation of gene expression patterns during differentiation of human multipotent cells, we analyzed expression status, histone modifications, and subnuclear positioning relative to repressive compartments, of hematopoietic loci in multipotent and lineage-committed primary human hematopoietic progenitors. We report here that positioning of lineage-affiliated loci relative to pericentromeric heterochromatin compartments (PCH) is identical in multipotent cells from various origins and is unchanged between multipotent and lineage-committed hematopoietic progenitors. However, during differentiation of multipotent hematopoietic progenitors, changes in gene expression and histone modifications at these loci occur in committed progenitors, prior to changes in gene positioning relative to pericentromeric heterochromatin compartments, detected at later stages in precursor and mature cells. Therefore, during normal human hematopoietic differentiation, changes in gene subnuclear location relative to pericentromeric heterochromatin appear to be dictated by whether the gene will be permanently silenced or activated, rather than being predictive of commitment toward a given lineage.
- Published
- 2009
- Full Text
- View/download PDF
40. Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells.
- Author
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Maës J, Maleszewska M, Guillemin C, Pflumio F, Six E, André-Schmutz I, Cavazzana-Calvo M, Charron D, Francastel C, and Goodhardt M
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Acetylation, Antigens, CD19 metabolism, Antigens, CD34 metabolism, Cell Differentiation, Cell Lineage, Fetal Blood cytology, Hematopoietic Stem Cells cytology, Humans, Lymphocytes cytology, Myeloid Cells cytology, Myeloid Cells metabolism, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle metabolism, Genes, Hematopoietic Stem Cells metabolism, Histones metabolism, Lymphocytes metabolism
- Abstract
To address the role of chromatin structure in the establishment of hematopoietic stem cell (HSC) multilineage potential and commitment to the lymphoid lineage, we have analyzed histone modifications at a panel of lymphoid- and myeloid-affiliated genes in multipotent and lineage-committed hematopoietic cells isolated from human cord blood. Our results show that many B- and T-lymphoid genes, although silent in HSCs, are associated with acetylated histones H3 and H4. We also detected histone H3 lysine 4 methylation but not repressive lysine 9 or 27 methylation marks at these loci, indicative of an open chromatin structure. Interestingly, the relative level of H3 lysine 4 dimethylation to trimethylation at B-specific loci was high in multipotent CD34(+)CD38(lo) progenitors and decreased as they become actively transcribed in B-lineage cells. In vitro differentiation of CD34(+) cells toward the erythroid, granulocyte, and T-cell lineages resulted in a loss of histone acetylation at nonlineage-associated genes. This study provides evidence that histone modifications involved in chromatin decondensation are already in place at lymphoid-specific genes in primary human HSCs, supporting the idea that these genes are "primed" for expression before lineage commitment. This permissive chromatin structure is progressively lost as the stem cell differentiates.
- Published
- 2008
- Full Text
- View/download PDF
41. Diurnal differences in melatonin effect on intracellular Ca2+ concentration in chicken spleen leukocytes in vitro.
- Author
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Wronka M, Maleszewska M, Stepińska U, and Markowska M
- Subjects
- Animals, Cells, Cultured, Gene Expression Regulation physiology, Male, Receptors, Melatonin biosynthesis, Receptors, Melatonin genetics, Receptors, Melatonin metabolism, Spleen cytology, Calcium metabolism, Chickens metabolism, Circadian Rhythm physiology, Intracellular Fluid metabolism, Leukocytes metabolism, Melatonin physiology, Spleen metabolism
- Abstract
Melatonin plays a pleiotropic role in the immune system of mammals and birds. Endogenous and exogenous melatonin modulates lymphocyte proliferation via specific MT(1), MT(2) and Mel(1c) membrane receptors, although the mechanisms behind this process are poorly understood. The diurnal changes in the expression and function of melatonin membrane receptors within the immune system have so far received little attention. We investigated the day/night differences in melatonin membrane receptor mRNA expression in chicken lymphoid organs and cultured splenocytes and examined the in vitro effect of melatonin and 2-iodomelatonin on the intracellular Ca(2+) concentration ([Ca(2+)](i)) in chicken splenocytes. In whole organs, expression of all subtypes of Mel membrane receptors was observed, and the level did not change significantly with the time of day. Interestingly, we observed a significant increase in the expression of the transcripts of all receptor subtypes in cultured splenocytes isolated at night compared with cells obtained during the day. In chicken spleen leukocytes isolated during the day, melatonin and 2-iodomelatonin increased [Ca(2+)](i), with only 2-iodomelatonin being effective in the 'night' cells. Luzindole modulated the [Ca(2+)](i) increase caused by melatonin receptor agonists: it potentiated the stimulatory effect of melatonin during the day, but counteracted that evoked by 2-iodomelatonin at night. The results of this study demonstrate that melatonin can induce changes in [Ca(2+)](i) in chicken spleen leukocytes that should modulate proliferation. The effect of melatonin on [Ca(2+)](i) is less pronounced at night, possibly caused by receptor desensitization.
- Published
- 2008
- Full Text
- View/download PDF
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