Consortium PSYCHIATRICUMConsortium PSYCHIATRICUMConsortium PSYCHIATRICUM2712-76722713-2919Eco-Vector21910.17816/CP219RESEARCHИССЛЕДОВАНИЕResearch ArticleDysregulation of Long Intergenic Non-Coding RNA Expression in the Schizophrenia BrainИзменения экспрессии длинных некодирующих РНК при шизофренииhttps://orcid.org/0000-0002-1703-0404NguyenTuanНгуенТуан
Russian Federation

MS

tuan.nguyen@skoltech.ruhttps://orcid.org/0000-0003-0842-3203EfimovaOlga I.ЕфимоваОльга Игоревна
Russian Federation

MS

o.efimova@skoltech.ruhttps://orcid.org/0000-0002-9234-5828TokarchukArtem V.ТокарчукАртем Валерьевич
Russian Federation

MS

a.tokarchuk@skoltech.ruhttps://orcid.org/0000-0002-8681-5299MorozovaAnna Yu.МорозоваАнна Юрьевна
Russian Federation

Senior Researcher, Department of Basic and Applied Neurobiology, The officer-in-charge

hakurate77@gmail.comhttps://orcid.org/0000-0003-0247-2717H-2424-20133017-3328ZorkinaYana A.ЗоркинаЯна Александровна
Russian Federation

Cand. Sci. (Biology), Senior Researcher

zorkina.ya@serbsky.ruhttps://orcid.org/0000-0002-3349-5391AndreyukDenis S.АндреюкДенис Сергеевич
Russian Federation

Cand. Sci. (Biology), Senior Fellow at the Education Center

denis.s.andreyuk@yandex.ruhttps://orcid.org/0000-0002-3073-630557200081884KostyukGeorge P.КостюкГеоргий Петрович
Russian Federation

Dr. Sci (Med.), Professor, Director, Editor-in-Chief, Consortium Psychiatricum

editorinchief@consortium-psy.comhttps://orcid.org/0000-0002-4305-0054KhaitovichPhilipp E.ХайтовичФилипп Ефимович
Russian Federation

Ph.D., Professor

p.khaitovich@skoltech.ruV. Zelman Center for Neurobiology and Brain Restoration, Skolkovo Institute of Science and TechnologyЦентр нейробиологии и нейрореабилитации имени Владимира Зельмана, АНОО ВО «Сколковский институт науки и технологий»V. Serbsky National Medical Research Centre of Psychiatry and Narcology of the Ministry of Health of the Russian FederationФГБУ «Национальный медицинский исследовательский центр психиатрии и наркологии им. В.П. Сербского» Минздрава РоссииMental-health Clinic No. 1 named after N.A. AlexeevГБУЗ «Психиатрическая клиническая больница № 1 им. Н.А. Алексеева Департамента здравоохранения города Москвы»0812202231032023415160910202207112022Copyright ©; 2023, Nguyen T., Efimova O.I., Tokarchuk A.V., Morozova A.Y., Zorkina Y.A., Andreyuk D.S., Kostyuk G.P., Khaitovich P.E.Copyright ©; 2023, Нгуен Т., Ефимова О.И., Токарчук А.В., Морозова А.Y., Зоркина Я.А., Андреюк Д.С., Костюк Г.П., Хайтович Ф.Е.2023Nguyen T., Efimova O.I., Tokarchuk A.V., Morozova A.Y., Zorkina Y.A., Andreyuk D.S., Kostyuk G.P., Khaitovich P.E.Нгуен Т., Ефимова О.И., Токарчук А.В., Морозова А.Y., Зоркина Я.А., Андреюк Д.С., Костюк Г.П., Хайтович Ф.Е.https://creativecommons.org/licenses/by-nc-nd/4.0/https://consortium-psy.com/jour/article/view/219

BACKGROUND: Transcriptomic studies of the brains of schizophrenia (SZ) patients have produced abundant but largely inconsistent findings about the disorder’s pathophysiology. These inconsistencies might stem not only from the heterogeneous nature of the disorder, but also from the unbalanced focus on particular cortical regions and protein-coding genes. Compared to protein-coding transcripts, long intergenic non-coding RNA (lincRNA) display substantially greater brain region and disease response specificity, positioning them as prospective indicators of SZ-associated alterations. Further, a growing understanding of the systemic character of the disorder calls for a more systematic screening involving multiple diverse brain regions.

AIM: We aimed to identify and interpret alterations of the lincRNA expression profiles in SZ by examining the transcriptomes of 35 brain regions.

METHODS: We measured the transcriptome of 35 brain regions dissected from eight adult brain specimens, four SZ patients, and four healthy controls, using high-throughput RNA sequencing. Analysis of these data yielded 861 annotated human lincRNAs passing the detection threshold.

RESULTS: Of the 861 detected lincRNA, 135 showed significant region-dependent expression alterations in SZ (two-way ANOVA, BH-adjusted p <0.05) and 37 additionally showed significant differential expression between HC and SZ individuals in at least one region (post hoc Tukey test, p <0.05). For these 37 differentially expressed lincRNAs (DELs), 88% of the differences occurred in a cluster of brain regions containing axon-rich brain regions and cerebellum. Functional annotation of the DEL targets further revealed stark enrichment in neurons and synaptic transmission terms and pathways.

CONCLUSION: Our study highlights the utility of a systematic brain transcriptome analysis relying on the expression profiles measured across multiple brain regions and singles out white matter regions as a prospective target for further SZ research.

ВВЕДЕНИЕ: Исследования транскриптома мозга пациентов с диагнозом шизофрении (ШЗ) не дали однозначной картины механизмов, лежащих в основе этого расстройства. Данная проблема связана не только с возможной гетерогенностью ШЗ, но также с несбалансированным фокусом исследований на определенных областях коры полушарий и экспрессии белок-кодирующих генов. По сравнению с белок-кодирующими генами, длинные некодирующие РНК (дкРНК) демонстрируют значительно большую специфичность и динамику паттернов экспрессии, что позиционирует их как перспективные маркеры молекулярных изменений мозга при ШЗ. Кроме того, растущее понимание системного характера ШЗ требует более систематического анализа экспрессии дкРНК, охватывающего множественные регионы мозга.

ЦЕЛЬ: Идентифицировать и интерпретировать изменения профилей экспрессии дкРНК при ШЗ в 35 регионах мозга.

МЕТОДЫ: Мы провели анализ транскриптома 35 областей мозга четырех пациентов с диагнозом ШЗ и четырех человек из группы контроля, используя высокопроизводительное секвенирование РНК.

РЕЗУЛЬТАТЫ: Из 861 детектированной дкРНК 135 продемонстрировали глобально значимые изменения уровней экспрессии при ШЗ (двусторонний дисперсионный анализ, скорректировано методом Бенджамини–Хохберга p <0,05). Из них 37 дкРНК показали значимые изменения, локализованные в одном или нескольких регионах мозга (тест Тьюки, p <0,05). Из этих изменений 88% произошли в регионах белого вещества мозга и мозжечке. Функциональная аннотация 37 дкРНК выявила значимую корреляцию с генами нейронов и генами, кодирующими элементы синаптической передачи сигнала.

ЗАКЛЮЧЕНИЕ: Наше исследование подчеркивает полезность систематического анализа транскриптома мозга и выделяет области белого вещества в качестве перспективной цели для дальнейших исследований ШЗ.

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