Biology subjects

Maleszewska, M.

Publications and source records attributed to Maleszewska, M..

3 recordsLinked to original sources

bioRxiv2022

Hypoxia promotes osteogenesis via regulation of the mito-nuclear communication

Bone marrow mesenchymal stem cells (MSCs) reside in a hypoxic niche that maintains their differentiation potential. Several studies have highlighted the critical role of hypoxia (low oxygen concentration) in the regulation of stem cell function, reporting differentiation defects following a switch to normoxia (high oxygen concentration). However, the molecular events triggering changes in stem cell fate decisions in response to high oxygen remain elusive. Here, we study the impact of normoxia in the mito-nuclear communication, with regards to stem cell differentiation. We show that normoxia-cultured 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 rewiring of metabolism, resulting in high acetyl-CoA levels, histone hypo-acetylation occurs due to trapping of acetyl-CoA inside mitochondria, likely due to lower CiC activity. Strikingly, restoring the cytosolic acetyl-CoA pool via acetate supplementation remodels the chromatin landscape and rescues the osteogenic defects. Collectively, our results demonstrate that the metabolism-chromatin-osteogenesis axis is heavily perturbed in response to high oxygen and identify CiC as a novel, oxygen-sensitive regulator of MSC function.

cell biology↗

bioRxiv2020

TOP2A substitution enhances topoisomerase activity and causes transcriptional dysfunction in glioblastoma patients

BackgroundHigh grade gliomas (HGGs) are aggressive, primary brain tumors with poor clinical outcomes. We aim to better understand glioma pathobiology and find potential therapeutic susceptibilities. MethodsWe designed a custom panel of 664 cancer- and epigenetics-related genes, and employed targeted next generation sequencing to study the genomic landscape of somatic and germline variants in 182 gliomas of different malignancy grades. mRNA sequencing was performed to detect transcriptomic abnormalities. ResultsIn addition to known alterations in TP53, IDH1, ATRX, EGFR genes found in this cohort, we identified a novel, recurrent mutation in the TOP2A gene coding for Topoisomerase 2A occurring only in glioblastomas (GBM, WHO grade IV gliomas). Biochemical assays with recombinant proteins demonstrated stronger DNA binding and DNA supercoil relaxation activities of the variant proteins. GBM patients carrying the mutated TOP2A had shorter overall survival than those with the wild type TOP2A. Computational analyses of transcriptomic data showed that GBMs with the mutated TOP2A have different transcriptomic patterns suggesting higher transcriptomic activity. ConclusionWe identified a novel TOP2A E948Q variant that strongly binds to DNA and is more active than the wild type protein. Our findings suggest that the discovered TOP2A variant is gain-of-function mutation. Key pointsO_LIThe most frequent genetic alterations in high grade gliomas are reported. C_LIO_LIA new mutation in the TOP2A gene was found in 4 patients from Polish population. C_LIO_LIA E948Q substitution changes TOP2A activities towards DNA. C_LIO_LIThe recurrent TOP2A variant is a gain-of-function mutation. C_LI Importance of the studyGlioblastoma is a deadly disease. Despite recent advancements in genomics and innovative targeted therapies, glioblastoma therapy has not shown improvements. Insights into glioblastoma biology may improve diagnosis, prognosis, and treatment prediction, directing to a better outcome. We performed targeted sequencing of 664 cancer genes, and identified a new variant of the TOP2A gene encoding topoisomerase 2A in glioblastomas. The TOP2A protein variant shows a higher affinity towards DNA and causes transcriptional alterations, suggesting a higher de novo transcription rate.

cancer biology↗

bioRxiv2020

Deregulated mito-nuclear communication alters chromatin plasticity and differentiation potential of mesenchymal stem cells upon ageing

Ageing is accompanied by a general decline in the function of many cellular pathways, with metabolic alterations, epigenetic modifications, and stem cell exhaustion representing three important hallmarks of the ageing process. However, whether these pathways are causally or functionally related at a molecular level remains poorly understood. Here, we use bone marrow-derived mesenchymal stem cells (MSCs) isolated from young and old mice to address how age-dependent changes in metabolism and epigenetics are linked and how they impact on the ageing transcriptome and differentiation potential. Given that MSCs maintain specific age-associated properties even under prolonged culture conditions, such as the age-dependent decrease in osteogenic differentiation, they are an excellent model to investigate in vitro the connection of ageing hallmarks on a mechanistic level. In this study, we demonstrate that upon ageing, osteogenic potential of MSCs declines as a consequence of deregulated mito-nuclear communication, mediated by decreased levels of the citrate carrier (CiC). Age-dependent down-regulation of CiC results in acetyl-CoA trapping within mitochondria, hypo-acetylation of histones and chromatin compaction. Together, these changes lead to an altered transcriptional output and are responsible for the reduced differentiation capacity into osteoblasts. Strikingly, short-term supplementation of aged cells with acetate, an exogenous source for cytosolic acetyl-CoA production, rescues not only the age-associated reduction of histone acetylation, but also the osteogenesis defect, representing a potential target for in vitro MSC rejuvenation.

cell biology↗