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000303494 1001_ $$00009-0009-7752-6215$$aBayer, Marc$$b0
000303494 245__ $$aChemotherapy (Etoposide)-Induced Intermingling of Heterochromatin and Euchromatin Compartments in Senescent PA-1 Embryonal Carcinoma Cells.
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000303494 520__ $$aBackground: Often, neoadjuvant therapy, which relies on the induction of double-strand breaks (DSBs), is used prior to surgery to shrink tumors by inducing cancer cell apoptosis. However, recent studies have suggested that this treatment may also induce a fluctuating state between senescence and stemness in PA-1 embryonal carcinoma cells, potentially affecting therapeutic outcomes. Thus, the respective epigenetic pathways are up or downregulated over a time period of days. These fluctuations go hand in hand with changes in spatial DNA organization. Methods: By means of Single-Molecule Localization Microscopy in combination with mathematical evaluation tools for pointillist data sets, we investigated the organization of euchromatin and heterochromatin at the nanoscale on the third and fifth day after etoposide treatment. Results: Using fluorescently labeled antibodies against H3K9me3 (heterochromatin tri-methylation sites) and H3K4me3 (euchromatin tri-methylation sites), we found that the induction of DSBs led to the de-condensation of heterochromatin and compaction of euchromatin, with a peak effect on day 3 after the treatment. On day 3, we also observed the co-localization of euchromatin and heterochromatin, which have marks that usually occur in exclusive low-overlapping network-like compartments. The evaluation of the SMLM data using topological tools (persistent homology and persistent imaging) and principal component analysis, as well as the confocal microscopy analysis of H3K9me3- and H3K4me3-stained PA-1 cells, supported the findings that distinct shifts in euchromatin and heterochromatin organization took place in a subpopulation of these cells during the days after the treatment. Furthermore, by means of flow cytometry, it was shown that the rearrangements in chromatin organization coincided with the simultaneous upregulation of the stemness promotors OCT4A and SOX2 and senescence promotors p21Cip1 and p27. Conclusions: Our findings suggest potential applications to improve cancer therapy by inhibiting chromatin remodeling and preventing therapy-induced senescence.
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000303494 650_7 $$2Other$$aDNA damage by etoposide
000303494 650_7 $$2Other$$acell-fate
000303494 650_7 $$2Other$$achromatin re-organization in tumor cells
000303494 650_7 $$2Other$$asenescence
000303494 650_7 $$2Other$$asingle-molecule localization microscopy
000303494 650_7 $$2Other$$astatistical and topological data evaluation
000303494 650_7 $$2Other$$astemness self-renewal
000303494 7001_ $$aZajakina, Jaroslava$$b1
000303494 7001_ $$aSchäfer, Myriam$$b2
000303494 7001_ $$aSalmina, Kristine$$b3
000303494 7001_ $$00000-0003-3745-3575$$aRumnieks, Felikss$$b4
000303494 7001_ $$00000-0003-0845-4392$$aJansons, Juris$$b5
000303494 7001_ $$0P:(DE-He78)89e155931400aa7bb80b79b6be41f979$$aBestvater, Felix$$b6$$udkfz
000303494 7001_ $$00000-0001-7188-9693$$aKurg, Reet$$b7
000303494 7001_ $$00000-0002-2870-7775$$aErenpreisa, Jekaterina$$b8
000303494 7001_ $$00000-0001-9430-1987$$aHausmann, Michael$$b9
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