1Q12 Loci Movement in the Interphase Nucleus Under the Action of ROS Is an Important Component of the Mechanism That Determines Copy Number Variation of Satellite III (1q12) in Health and Schizophrenia

Marina Sergeevna Konkova; Elizaveta Sergeevna Ershova; Ekaterina Alekseevna Savinova; Elena Mikhailovna Malinovskaya; Galina Vasilievna Shmarina; Andrey Vladimirovich Martynov; Roman Vladimirovich Veiko; Nataly Vyacheslavovna Zakharova; Pavel Umriukhin; Georgy Petrovich Kostyuk; Vera Leonidovna Izhevskaya; Sergey Ivanovich Kutsev; Natalia Nikolaevna Veiko; Svetlana Victorovna Kostyuk

doi:10.3389/fcell.2020.00386

1Q12 Loci Movement in the Interphase Nucleus Under the Action of ROS Is an Important Component of the Mechanism That Determines Copy Number Variation of Satellite III (1q12) in Health and Schizophrenia

Front Cell Dev Biol. 2020 Jun 5:8:386. doi: 10.3389/fcell.2020.00386. eCollection 2020.

Authors

Marina Sergeevna Konkova¹, Elizaveta Sergeevna Ershova¹, Ekaterina Alekseevna Savinova¹, Elena Mikhailovna Malinovskaya¹, Galina Vasilievna Shmarina¹, Andrey Vladimirovich Martynov¹, Roman Vladimirovich Veiko¹, Nataly Vyacheslavovna Zakharova², Pavel Umriukhin^{1

3

4}, Georgy Petrovich Kostyuk², Vera Leonidovna Izhevskaya¹, Sergey Ivanovich Kutsev¹, Natalia Nikolaevna Veiko¹, Svetlana Victorovna Kostyuk¹

Affiliations

¹ Federal State Budgetary Scientific Institution, Research Centre for Medical Genetics, Moscow, Russia.
² N.A. Alekseev Clinical Psychiatric Hospital No 1, Moscow Healthcare Department, Moscow, Russia.
³ I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia.
⁴ P.K. Anokhin Institute of Normal Physiology, Moscow, Russia.

Abstract

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.

Keywords: 1q12; CNVs; rDNA; satellite III; schizophrenia.