Jakub Mieczkowski

Jakub Mieczkowski
Medical University of Gdansk | MUG · International Research Agenda 3P

PhD

About

104
Publications
11,754
Reads
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1,703
Citations
Additional affiliations
October 2008 - March 2013
Nencki Institute of Experimental Biology
Position
  • PhD Student

Publications

Publications (104)
Preprint
Full-text available
Normal-appearing mammary tissue from breast cancer patients can harbor significant genetic alterations. We analyzed DNA variants in both normal-looking tissue and tumors from 77 poor-prognosis patients, 49 patients without prognosis bias, and mammary gland samples from 15 non-cancerous individuals. Whole exome sequencing revealed a higher prevalenc...
Preprint
Full-text available
The p53 tumor suppressor is an indispensable regulator of DNA damage responses that accelerates carcinogenesis when mutated. In this report, we uncover a new mechanism by which p53 maintains genomic integrity in the absence of canonical DNA damage response activation. Specifically, loss of p53 dramatically alters chromatin structure at the nuclear...
Preprint
Hypoxia rapidly alters gene expression to allow cellular adaptation to challenging conditions and support tumour growth. Hypoxia also affects the chromatin structure by modifications of histones and DNA methylation. Glioblastoma (GBM) is an aggressive, deadly primary brain tumour for which there is no effective treatment. The tumour microenvironmen...
Article
The reduced ability of the central nervous system to regenerate with increasing age limits functional recovery following demyelinating injury. Previous work has shown that myelin debris can overwhelm the metabolic capacity of microglia, thereby impeding tissue regeneration in aging, but the underlying mechanisms are unknown. In a model of demyelina...
Article
Full-text available
Despite advances in early detection and treatment strategies, breast cancer recurrence and mortality remain a significant health issue. Recent insights suggest the prognostic potential of microscopically healthy mammary gland, in the vicinity of the breast lesion. Nonetheless, a comprehensive understanding of the gene expression profiles in these t...
Article
The hierarchical chromatin organization begins with formation of nucleosomes, which fold into chromatin domains punctuated by boundaries and ultimately chromosomes. In a hierarchal organization, lower levels shape higher levels. However, the dependence of higher-order 3D chromatin organization on the nucleosome-level organization has not been studi...
Article
Full-text available
As the most prescribed psychotropic drugs in current medical practice, antidepressant drugs (ADs) of the selective serotonin reuptake inhibitor (SSRI) class represent prime candidates for drug repurposing. The mechanisms underlying their mode of action, however, remain unclear. Here, we show that common SSRIs and selected representatives of other A...
Article
Full-text available
Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematologi...
Article
Full-text available
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...
Preprint
Full-text available
Despite advances in early detection and treatment strategies, breast cancer recurrence and mortality remain a significant health issue. Recent insights suggest the prognostic potential of microscopically healthy mammary gland, in the vicinity of the breast lesion. Nonetheless, a comprehensive understanding of the gene expression profiles in these t...
Article
Full-text available
Despite surging interest in space travel in recent decades, the impacts of prolonged, elevated exposure to galactic cosmic radiation (GCR) on human health remain poorly understood. This form of ionizing radiation causes significant changes to biological systems including damage to DNA structure by altering epigenetic phenotype with emphasis on DNA...
Preprint
Full-text available
Male sex is a risk factor for colorectal cancer (CRC) with higher illness burden and earlier onset. Thus, we hypothesized that loss of chromosome Y (LOY) in the tumor micro-environment (TME) might be involved in oncogenesis. Previous studies show that LOY in circulating leukocytes of aging men was associated with shorter survival and non-hematologi...
Article
Full-text available
Diffuse midline gliomas (DMGs) are the most challenging to treat pediatric high-grade gliomas, with a dismal prognosis of 9 to 15 months of median survival. The ones localized in the pons are not accessible to the surgery and rely on radiotherapy treatment. The majority of DMGs confer a mutation in histone 3 variants (H3.3 or H3.1), leading to lysi...
Preprint
Full-text available
Diffuse intrinsic pontine gliomas (DIPG) are deadly paediatric brain tumours, non-resectable due to brainstem localisation and diffusive growth. Patients with DIPG have a dismal prognosis of 9-12 months of survival with no effective therapy. Over 80% of DIPGs harbour a mutation in histone 3 (H3.3 or H3.1) resulting in a lysine to methionine substit...
Article
Full-text available
Local hypoxia occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most research has focused on hypoxia-inducible genes as opposed to those which are decreased in hypoxia. We demonstrate that chromatin...
Article
Full-text available
Background: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickne...
Article
Full-text available
Chromatin attains its three-dimensional (3D) conformation by establishing contacts between different noncontiguous regions. Sterile Alpha Motif (SAM)-mediated polymerization of the polyhomeotic (PH) protein regulates subnuclear clustering of Polycomb Repressive Complex 1 (PRC1) and chromatin topology. The mutations that perturb the ability of the P...
Preprint
Full-text available
Despite surging interest in space travel in recent decades, the impacts of prolonged, elevated exposure to galactic cosmic radiation (GCR) on human health remain poorly understood. This form of ionizing radiation causes significant changes to biological systems including damage to DNA structure by altering epigenetic phenotype with emphasis on DNA...
Preprint
Alzheimer's disease (AD) is a common and increasing societal problem due to the extending human lifespan. In males, loss of Y (LOY) in leukocytes is more prevalent in AD patients. We studied DNA methylation, gene expression and other epigenetic changes in monocytes and granulocytes with and without LOY from male AD patients and controls. We show th...
Preprint
Full-text available
Background: Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thicknes...
Article
Full-text available
Numeric sex chromosome abnormalities are commonly associated with an increased cancer risk. Here, we report a 14-year-old boy with a rare mosaic 45, X/48, XYYY karyotype presenting with subtle dysmorphic features and relative height deficiency, requiring growth hormone therapy. As only 12 postnatal cases have been described so far with very limited...
Article
Full-text available
Glioblastoma (GBM), a deadly brain tumor, is still one of the few lasting challenges of contemporary oncology. Current therapies fail to significantly improve patient survival due to GBM’s tremendous genetic, transcriptomic, immunological, and sex-dependent heterogeneity. Over the years, clinical differences between males and females were character...
Preprint
Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover new modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tissu...
Preprint
Local hypoxia (low oxygen) occurs in most solid tumors and is associated with aggressive disease and therapy resistance. Widespread changes in gene expression play a critical role in the biological response to hypoxia. However, most of the prior research has focused on hypoxia-inducible genes in hypoxia as opposed to those which are decreased. Usin...
Preprint
Full-text available
Visium Spatial Gene Expression (ST) is a method combining histological spatial information with transcriptomics profiles directly from tissue sections. The use of spatial information has made it possible to discover novel modes of gene expression regulations. However, in the ST experiment, the nucleus size of cells may exceed the thickness of a tis...
Article
Full-text available
Chronic and acute myeloid leukemia (CML, AML) evade immune system surveillance and induce immunosuppression by expanding pro-leukemic Foxp3+ regulatory T cells (Tregs). High levels of immunosuppressive Tregs predict inferior response to chemotherapy, leukemia relapse and shorter survival. However, mechanisms that promote Tregs in myeloid leukemias...
Article
Full-text available
Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brainstem, DIPGs are difficult to resect and rapidly tur...
Article
BACKGROUND Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most aggressive type of primary brain tumor. GBM has the poorest prognosis with no efficient cure to date due to diffusive growth into the brain, resistance to treatments and the immunosuppressive tumor microenvironment (TME). The growth and invasiven...
Article
Full-text available
Chromatin structure is often dysregulated in cancers, including glioblastoma (GBM), the most common primary brain tumor in adults. GBM has the poorest prognosis and no efficient cure to date due to diffusive growth into the surrounding brain, preventing complete surgical resection and leading to inevitable tumor relapse. Tumor microenvironment (TME...
Article
Full-text available
Malignant gliomas represent over 70% of primary brain tumors and the most deadly is glioblastoma (GBM, WHO grade IV), due to frequent dysfunctions of tumor suppressors or/and oncogenes. Recent whole genome studies of gliomas demonstrated that besides genetic alterations, epigenetic dysfunctions contribute to tumor development and progression. Alter...
Article
Full-text available
Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer develop...
Article
Full-text available
Microglia are resident myeloid cells in the central nervous system (CNS) that control homeostasis and protect CNS from damage and infections. Microglia and peripheral myeloid cells accumulate and adapt tumor supporting roles in human glioblastomas that show prevalence in men. Cell heterogeneity and functional phenotypes of myeloid subpopulations in...
Article
Full-text available
Accumulating evidence suggests that glioma stem cells (GSCs), which are rare cells characterized by pluripotency and self-renewal ability, are responsible for glioblastoma (GBM) propagation, recurrence and resistance to therapies. Bone morphogenic proteins (BMPs) induce GSC differentiation, which leads to elimination of GSCs and sensitization of gl...
Article
Full-text available
Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to support remyelinati...
Preprint
Full-text available
Chromatin structure and accessibility, and combinatorial binding of transcription factors to regulatory elements in genomic DNA control transcription. Genetic variations in genes encoding histones, epigenetics-related enzymes or modifiers affect chromatin structure/dynamics and result in alterations in gene expression contributing to cancer develop...
Conference Paper
Glioblastoma (GBM) is the most aggressive primary brain tumor showing the poorest prognosis. Despite extensive research, no significant improvement in glioma therapy. GBM microenvironment has been shown to contribute to the aggressiveness of the tumor and influences overall survival. Tumor associated microglia and macrophages (TAMs) contribute to t...
Preprint
Full-text available
Brain resident and infiltrating innate immune cells adapt a tumor-supportive phenotype in the glioma microenvironment. Flow cytometry analysis supported by a single-cell RNA sequencing study of human gliomas indicate considerable cell type heterogeneity. It remains disputable whether microglia and infiltrating macrophages have the same or distinct...
Article
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 unkno...
Article
Background Glioma is the most common primary brain tumour and often confers a grave prognosis. In low-grade gliomas seizures occur frequently (70–80%) and usually are pharmacoresistant. While genes coding for interleukins and implicated in neurotransmitters signalling have been associated with focal seizures, a molecular profile of glioma-associate...
Article
Full-text available
Following CNS demyelination, oligodendrocyte progenitor cells (OPCs) are able to differentiate into either remyelinating oligodendrocytes (OLs) or remyelinating Schwann cells (SCs). However, the signals that determine which type of remyelinating cell is generated and the underlying mechanisms involved have not been identified. Here, we show that di...
Data
Genes significantly regulated in the vascular niche. Dots represent level of expression for individual animal sample.
Data
Genes significantly regulated in the non-vascular areas. Dots represent level of expression for individual animal sample.
Data
Genes significantly regulated only in the vascular niche. Dots represent level of expression for individual animal sample.
Chapter
Assays profiling nucleosome positioning and occupancy are often coupled with high-throughput sequencing, which results in generation of large data sets. These data sets require processing in specialized computational pipelines to yield useful information. Here, we describe main steps of such a pipeline, and discuss bioinformatic and statistical asp...
Article
Full-text available
Immune cells accumulating in the microenvironment of malignant tumors are tumor educated and contribute to its growth, progression, and evasion of antitumor immune responses. Glioblastoma (GBM), the common and most malignant primary brain tumor in adults, shows considerable accumulation of resident microglia and peripheral macrophages, and their po...
Data
Correlation of gene expression patterns in various datasets. A heatmap shows Spearman’s correlation coefficients between microglia activation (log2 fold changes) for samples collected from human, mouse, and rat samples.
Data
Western blot analysis of total extracts from microglia polarized with glioma cells for active components of transforming growth factor beta signaling pathway revealed the increased levels of active, phosphorylated SMAD2 proteins accumulating at 3 and 6 h after glioma-conditioned medium (GCM) treatment. Immunoblots were stripped and re-probed first...
Data
Matrigel assay was performed to determine invasion of different human glioma cells in the presence of SV40 immortalized human microglia. Data are calculated as fold change in relation to basal invasion in the absence of microglia. Matrigel invasion data are calculated as means ± SD, n = 3 and were analyzed by one-sided paired sample t-test; n ≥ 3....
Data
Microarray gene expression validation. Five genes were selected for validation of the microarray gene expression analysis (Tgm2, Cx3cr1, Tgfbi, Tmem37, and Socs2). Expression is presented as delta Ct values in control, glioma-conditioned medium (GCM) LN18, and GCM U87-MG treated for 6 h. Validation was performed on separate experiments n = 4; **p <...
Conference Paper
Full-text available
Introduction Personalised oncology revolutionises the way how eligible therapies are selected to treat cancer patients. With the help of next-generation sequencing technology, cancer can be understood at the molecular level. This enables clinicians to match cancer patients to drugs that precisely target the driver mutations of the tumour. The found...
Conference Paper
Full-text available
Introduction Glioblastoma (GBM) is the most aggressive primary brain tumour, with a median patient survival of 14 months. Accumulating evidence suggests that glioma stem-like cells (GSCs) are responsible for glioblastoma propagation, recurrence and resistance to therapy. Differentiation therapy is consider as a promising approach to eliminate this...
Article
Full-text available
In glioma, microglia and infiltrating macrophages are exposed to factors that force them to produce cytokines and chemokines, contributing to tumor growth and maintaining a pro-tumorigenic, immunosuppressed microenvironment. We demonstrate that housing glioma-bearing mice in enriched environment (EE) reverts the immunosuppressive phenotype of infil...
Data
Raw data and detailed statistical analysis report. Raw data of Gene Ontology over-representation analysis (Bonferroni corrected p-values <0.05) of the genes that are upregulated in microglia after EE exposure.Image: raw data refer to Figure 1 data.
Article
Full-text available
Glioblastoma (GBM) is the most aggressive primary brain tumor, with ineffective anti-tumor responses and a poor prognosis despite aggressive treatments. GBM immune microenvironment is heterogenous and activation of specific immune populations in GBM is not fully characterized. Reliable animal models are critical for defining mechanisms of anti-tumo...
Chapter
This unit describes a method for determining the accessibility of chromatinized DNA and nucleosome occupancy in the same assay. Enzymatic digestion of chromatin using micrococcal nuclease (MNase) is optimized for liberation, retrieval, and characterization of DNA fragments from chromatin. MNase digestion is performed in a titration series, and the...
Article
Full-text available
Activation of transcription requires alteration of chromatin by complexes that increase the accessibility of nucleosomal DNA. Removing nucleosomes from regulatory sequences has been proposed to play a significant role in activation. We tested whether changes in nucleosome occupancy occurred on the set of genes that is activated by the unfolded prot...
Article
Full-text available
SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having ind...
Data
Top 1000 regions with highest turnover in ESCs. DOI: http://dx.doi.org/10.7554/eLife.15316.021
Data
Top 1000 regions with highest turnover in NSCs. DOI: http://dx.doi.org/10.7554/eLife.15316.022
Data
Primer sequences. DOI: http://dx.doi.org/10.7554/eLife.15316.026
Data
External datasets used. DOI: http://dx.doi.org/10.7554/eLife.15316.024
Data
Spike-in controls. DOI: http://dx.doi.org/10.7554/eLife.15316.025
Data
Differences in turnover between ESCs and NSCs. DOI: http://dx.doi.org/10.7554/eLife.15316.023
Article
Full-text available
Chromatin accessibility plays a fundamental role in gene regulation. Nucleosome placement, usually measured by quantifying protection of DNA from enzymatic digestion, can regulate accessibility. We introduce a metric that uses micrococcal nuclease (MNase) digestion in a novel manner to measure chromatin accessibility by combining information from s...
Data
Supplementary Figures 1-26 and Supplementary Tables 1-2