vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-22-29vavilov-3356Research ArticleМОЛЕКУЛЯРНАЯ И КЛЕТОЧНАЯ БИОЛОГИЯMOLECULAR AND CELL BIOLOGYЭкспериментальное изучение влияния SNP ТАТА-боксов генов GRIN1, ASCL3 и NOS1 на взаимодействие с ТАТА-связывающим белкомAn experimental study of the effects of SNPs in the TATA boxes of the GRIN1, ASCL3 and NOS1 genes on interactions with the TATA-binding proteinhttps://orcid.org/0000-0002-1467-9312ШарыповаЕ. Б.SharypovaE. B.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-2522-1657ДрачковаИ. А.DrachkovaI. A.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-2724-5441ЧадаеваИ. В.ChadaevaI. V.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-1663-318XПономаренкоМ. П.PonomarenkoM. P.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-4543-4104СавинковаЛ. К.SavinkovaL. K.

Новосибирск

Novosibirsk

savinkl@mail.ruФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202203062022263227233Copyright © Шарыпова Е.Б., Драчкова И.А., Чадаева И.В., Пономаренко М.П., Савинкова Л.К., 20222022Шарыпова Е.Б., Драчкова И.А., Чадаева И.В., Пономаренко М.П., Савинкова Л.К.Sharypova E.B., Drachkova I.A., Chadaeva I.V., Ponomarenko M.P., Savinkova L.K.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3356

Гены GRIN1, ASCL3 и NOS1 связаны с различными фенотипами нервно-психических расстройств. Эти гены делают вклад в развитие шизофрении, болезней Альцгеймера и Паркинсона, эпилепсии и др. и ассоциируются также с различными онкологическими заболеваниями. Например, повышенная экспрессия ASCL3 наблюдается при раке молочной железы, NOS1 – в клеточных линиях рака яичников. Ранее на основе наших и литературных данных мы получили результаты, свидетельствующие в пользу того, что SNP, нарушающие эритропоэз, с большой вероятностью могут быть связаны с когнитивными и нервно-психическими расстройствами у человека. В настоящей работе исследовано влияние выявленных с помощью SNP_TATA_Z-tester не аннотированных SNP ТАТА-боксов промоторов генов GRIN1, ASCL3 и NOS1, участвующих в нервно-психических расстройствах и онкологических заболеваниях, на взаимодействие ТАТА-связывающего белка (ТВР). Для изучения in vitro кинетических характеристик образования комплексов ТВР/ТАТА и аффинности с помощью метода задержки ДНК в геле использованы двуцепочечные олигодезоксирибонуклеотиды, идентичные ТАТА-содержащим участкам промоторов генов GRIN1, ASCL3 и NOS1 (референсным и минорным аллелям), и рекомбинантный ТВР человека. Показано, например, что аллель «A» rs1402667001 промотора гена GRIN1 повышает аффинность ТВР/ТАТА в 1.4 раза, а аллель «С» ТАТА-бокса промотора гена ASCL3 снижает аффинность в 1.4 раза; при этом время жизни комплексов в обоих случаях уменьшается примерно на 20 % за счет изменения скоростей образования и диссоциации комплексов (ka и kd соответственно). Наши экспериментальные результаты согласуются с литературными данными, показывающими низкую экспрессию гена GRIN1 при шизофренических расстройствах и повышенный риск возникновения рака шейки матки, мочевого пузыря, почек и лимфомы при пониженной экспрессии гена АSCL3. Влияние аллеля «А» SNP –27G>A (rs1195040887) промотора гена NOS1 гипотетически может свидетельствовать о повышенном риске возникновения ишемического повреждения мозга у носителей. Сравнение экспериментальных значений аффинности (KD) ТВР/ТАТА «диких» (WT) и минорных аллелей c прогнозируемыми показало, что данные хорошо коррелируют друг с другом: коэффициент линейной корреляции r = 0.94 ( p < 0.01).

The GRIN1, ASCL3, and NOS1 genes are associated with various phenotypes of neuropsychiatric disorders. For instance, these genes contribute to the development of schizophrenia, Alzheimer’s and Parkinson’s diseases, and epilepsy. These genes are also associated with various cancers. For example, ASCL3 is overexpressed in breast cancer, and NOS1, in ovarian cancer cell lines. Based on our findings and literature data, we had previously obtained results suggesting that the single-nucleotide polymorphisms (SNPs) that disrupt erythropoiesis are highly likely to be associated with cognitive and neuropsychiatric disorders in humans. In the present work, using SNP_TATA_Z-tester, we investigated the influence of unannotated SNPs in the TATA boxes of the promoters of the GRIN1, ASCL3, and NOS1 genes (which are involved in neuropsychiatric disorders and cancers) on the interaction of the TATA boxes with the TATA-binding protein (TBP). Double-stranded oligodeoxyribonucleotides identical to the TATA-containing promoter regions of the GRIN1, ASCL3, and NOS1 genes (reference and minor alleles) and recombinant human TBP were employed to study in vitro (by an electrophoretic mobility shift assay) kinetic characteristics of the formation of TBP–TATA complexes and their affinity. It was found, for example, that allele A of rs1402667001 in the GRIN1 promoter increases TBP–TATA affinity 1.4-fold, whereas allele C in the TATA box of the ASCL3 promoter decreases the affinity 1.4-fold. The lifetime of the complexes in both cases decreased by ~20 % due to changes in the rates of association and dissociation of the complexes (ka and kd, respectively). Our experimental results are consistent with the literature showing GRIN1 underexpression in schizophrenic disorders as well as an increased risk of cervical, bladder, and kidney cancers and lymphoma during ASCL3 underexpression. The effect of allele A of the –27G>A SNP (rs1195040887) in the NOS1 promoter is suggestive of an increased risk of ischemic damage to the brain in carriers. A comparison of experimental TBP–TATA affinity values (KD) of wild-type and minor alleles with predicted ones showed that the data correlate well (linear correlation coefficient r = 0.94, p < 0.01).

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The authors declare that there are no conflicts of interest present.