Dataset Information

Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts.

ABSTRACT: The fragment of satellite III (f-SatIII) is located in pericentromeric heterochromatin of chromosome 1. Cell with an enlarged f-SatIII block does not respond to various stimuli and are highly stress-susceptible. The fraction of f-SatIII in the cells of schizophrenia patients changed during antipsychotic therapy. Therefore, antipsychotics might reduce the f-SatIII content in the cells. We studied the action of haloperidol, risperidone and olanzapine (3 h, 24 h, 96 h) on human skin fibroblast lines (n = 10). The f-SatIII contents in DNA were measured using nonradioactive quantitative hybridization. RNASATIII were quantified using RT-qPCR. The levels of DNA damage markers (8-oxodG, γ-H2AX) and proteins that regulate apoptosis and autophagy were determined by flow cytometry. The antipsychotics reduced the f-SatIII content in DNA and RNASATIII content in RNA from HSFs. After an exposure to the antipsychotics, the autophagy marker LC3 significantly increased, while the apoptosis markers decreased. The f-SatIII content in DNA positively correlated with RNASATIII content in RNA and with DNA oxidation marker 8-oxodG, while negatively correlated with LC3 content. The antipsychotics arrest the process of f-SatIII repeat augmentation in cultured skin fibroblasts via the transcription suppression and/or through upregulated elimination of cells with enlarged f-SatIII blocks with the help of autophagy.

SUBMITTER: Ershova ES

PROVIDER: S-EPMC10380077 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts.

Ershova Elizaveta S ES Savinova Ekaterina A EA Kameneva Larisa V LV Porokhovnik Lev N LN Veiko Roman V RV Salimova Tatiana A TA Izhevskaya Vera L VL Kutsev Sergey I SI Veiko Natalia N NN Kostyuk Svetlana V SV

International journal of molecular sciences 20230710 14

The fragment of satellite III (f-SatIII) is located in pericentromeric heterochromatin of chromosome 1. Cell with an enlarged f-SatIII block does not respond to various stimuli and are highly stress-susceptible. The fraction of f-SatIII in the cells of schizophrenia patients changed during antipsychotic therapy. Therefore, antipsychotics might reduce the f-SatIII content in the cells. We studied the action of haloperidol, risperidone and olanzapine (3 h, 24 h, 96 h) on human skin fibroblast line ...[more]

PMID: 37511043

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Project description:Introduction: Human satellite DNA is organized in long arrays in peri/centromeric heterochromatin. There is little information about satellite copy number variants (CNVs) in aging and replicative cell senescence (RS). Materials and Methods: Biotinylated pUC1.77 probe was used for the satellite III (f-SatIII) quantitation in leukocyte DNA by the non-radioactive quantitative hybridization for 557 subjects between 2 and 91 years old. The effect of RS and genotoxic stress (GS, 4 or 6 µM of K2CrO4) on the f-SatIII CNV was studied on the cultured human skin fibroblast (HSF) lines of five subjects. Results: f-SatIII in leukocyte and HSFs varies between 5.7 and 40 pg/ng of DNA. During RS, the f-SatIII content in HSFs increased. During GS, HSFs may increase or decrease f-SatIII content. Cells with low f-SatIII content have the greatest proliferative potential. F-SatIII CNVs in different individuals belonging to the different generations depend on year of their birth. Children (born in 2005-2015 years) differed significantly from the other age groups by low content and low coefficient of variation of f-SatIII. In the individuals born in 1912-1925 and living in unfavorable social conditions (FWW, the Revolution and the Russian Civil War, SWW), there is a significant disproportion in the content of f-SatIII. The coefficient of variation reaches the maximum values than in individuals born in the period from 1926 to 1975. In the group of people born in 1990-2000 (Chernobyl disaster, the collapse of the Soviet Union, and a sharp decline in the population living standard), again, there is a significant disproportion of individuals in the content of f-SatIII. A similar disproportion was observed in the analysis of a group of individuals born in 1926-1975 who in their youth worked for a long time in high-radioactive environment. Conclusion: In generations that were born and who lived in childhood in a period of severe social perturbations or in conditions of environmental pollution, we found a significant increase in leukocyte DNA f-SatIII variability. It is hypothesized that the change of the f-SatIII content in the blood cells reflects the body response to stress of different nature and intensity.

Project description:Introduction: It was shown that copy number variations (CNVs) of human satellite III (1q12) fragment (f-SatIII) reflects the human cells response to stress of different nature and intensity. Patients with schizophrenia (SZ) experience chronic stress. The major research question: What is the f-SatIII CNVs in human leukocyte as a function of SZ? Materials and Methods: Biotinylated pUC1.77 probe was used for f-SatIII quantitation in leukocyte DNA by the non-radioactive quantitative hybridization for SZ patients (N = 840) and healthy control (HC, N = 401). SZ-sample included four groups. Two groups: first-episode drug-naïve patients [SZ (M-)] and medicated patients [SZ (M+)]. The medical history of these patients did not contain reliable confirmed information about fetal hypoxia and obstetric complications (H/OCs). Two other groups: medicated patients with documented H/OCs [hypoxia group (H-SZ (M+)] and medicated patients with documented absence of H/OCs [non-hypoxia group (NH-SZ (M+)]. The content of f-SatIII was also determined in eight post-mortem brain tissues of one SZ patient. Results: f-SatIII in human leukocyte varies between 5.7 to 44 pg/ng DNA. f-SatIII CNVs in SZ patients depends on the patient's history of H/OCs. f-SatIII CN in NH-SZ (M+)-group was significantly reduced compared to H-SZ (M+)-group and HC-group (p < 10-30). f-SatIII CN in SZ patients negatively correlated with the index reflecting the seriousness of the disease (Positive and Negative Syndrome Scale). Antipsychotic therapy increases f-SatIII CN in the untreated SZ patients with a low content of the repeat and reduces the f-SatIII CN in SZ patients with high content of the repeat. In general, the SZ (M+) and SZ (M-) groups do not differ in the content of f-SatIII, but significantly differ from the HC-group by lower values of the repeat content. f-SatIII CN in the eight regions of the brain of the SZ patient varies significantly. Conclusion: The content of f-SatIII repeat in leukocytes of the most patients with SZ is significantly reduced compared to the HC. Two hypotheses were put forward: (1) the low content of the repeat is a genetic feature of SZ; and/or (2) the genomes of the SZ patients respond to chronic oxidative stress reducing the repeats copies number.

Project description:Introduction: Genome repeat cluster sizes can affect the chromatin spatial configuration and function. Low-dose ionizing radiation (IR) induces an adaptive response (AR) in human cells. AR includes the change in chromatin spatial configuration that is necessary to change the expression profile of the genome in response to stress. The 1q12 heterochromatin loci movement from the periphery to the center of the nucleus is a marker of the chromatin configuration change. We hypothesized that a large 1q12 domain could affect chromatin movement, thereby inhibiting the AR. Materials and Methods: 2D fluorescent in situ hybridization (FISH) method was used for the satellite III fragment from the 1q12 region (f-SatIII) localization analysis in the interphase nuclei of healthy control (HC) lymphocytes, schizophrenia (SZ) patients, and in cultured mesenchymal stem cells (MSCs). The localization of the nucleolus was analyzed by the nucleolus Ag staining. The non-radioactive quantitative hybridization (NQH) technique was used for the f-SatIII fragment content in DNA analysis. Satellite III fragments transcription was analyzed by reverse transcriptase quantitative PCR (RT-qPCR). Results: Low-dose IR induces the small-area 1q12 domains movement from the periphery to the central regions of the nucleus in HC lymphocytes and MSCs. Simultaneously, nucleolus moves from the nucleus center toward the nuclear envelope. The nucleolus in that period increases. The distance between the 1q12 domain and the nucleolus in irradiated cells is significantly reduced. The large-area 1q12 domains do not move in response to stress. During prolonged cultivation, the irradiated cells with a large f-SatIII amount die, and the population is enriched with the cells with low f-SatIII content. IR induces satellite III transcription in HC lymphocytes. Intact SZ patients' lymphocytes have the same signs of nuclei activation as irradiated HC cells. Conclusion: When a cell population responds to stress, cells are selected according to the size of the 1q12 domain (the f-SatIII content). The low content of the f-SatIII repeat in SZ patients may be a consequence of the chronic oxidative stress and of a large copies number of the ribosomal repeats.

Dataset Information

Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts.

Publications

Antipsychotics Affect Satellite III (1q12) Copy Number Variations in the Cultured Human Skin Fibroblasts.

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