Эпигенетические изменения при посттравматическом стрессовом расстройстве: возможности и ограничения эпигенетической терапии

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Аннотация

В последние десятилетия во всем мире нарастающее давление экстремальных стрессогенных воздействий, угрожающих жизни индивидуума, существенно повысило частоту психических и поведенческих расстройств. Одно из наиболее тяжелых последствий переживания психотравмирующих ситуаций — развитие посттравматического стрессового расстройства. Применяемые в настоящее время терапевтические подходы помогают лишь небольшой части таких пациентов, и достаточно часто наблюдается высокий уровень отсутствия ответа и рецидивов. Возможными причинами неэффективности терапии в данном случае являются не только генетические, но и эпигенетические факторы, которые могут определять индивидуальные особенности фармакокинетики и фармакодинамики используемых препаратов.

В обзоре описаны эпигенетические механизмы, которые могут обусловливать индивидуальные различия в резистентности, риске развития и тяжести течения посттравматического стрессового расстройства. В краткой форме изложена информация о роли метилирования ДНК, модификаций гистонов, некодирующих РНК, ремоделирования хроматина и пространственной архитектуры генома при посттравматических и связанных со стрессом расстройств. Приведены данные о потенциальном использовании эпигенетических модификаций в качестве биомаркеров травматического стресса и факторов, отвечающих за наследование потомками негативных последствий психогенной травмы, перенесенной родителями. Обсуждаются возможности применения и ограничения эпигенетической терапии посттравматических стрессовых расстройств.

Об авторах

Ирина Олеговна Сучкова

Институт экспериментальной медицины

Автор, ответственный за переписку.
Email: irsuchkova@mail.ru
ORCID iD: 0000-0003-2127-0459
SPIN-код: 4155-7314

канд. биол. наук

Россия, Санкт-Петербург

Евгений Львович Паткин

Институт экспериментальной медицины

Email: elp44@mail.ru
ORCID iD: 0000-0002-6292-4167
SPIN-код: 4929-4630

д-р биол. наук, профессор

Россия, Санкт-Петербург

Сергей Георгиевич Цикунов

Институт экспериментальной медицины

Email: secikunov@yandex.ru
ORCID iD: 0000-0002-7097-1940
SPIN-код: 7771-1940

д-р мед. наук, профессор

Россия, Санкт-Петербург

Генрих Александрович Софронов

Институт экспериментальной медицины; Военно-медицинская академия имени С.М. Кирова

Email: gasofronov@mail.ru
ORCID iD: 0000-0002-8587-1328
SPIN-код: 7334-4881

д-р мед. наук, профессор, академик РАН

Россия, Санкт-Петербург; Санкт-Петербург

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2. Рис. 1. Схема эпигенетических механизмов регуляции экспрессии генов у эукариот. A, G, T, C — азотистые основания (аденин, гуанин, тимин, цитозин); DNMTs — ДНК-метилтрансферазы; UHRF1 — убиквитин-подобный белок, содержащий домены PHD и безымянный палец; TETs — белки из семейства «транслокаций десять-одиннадцать» метилцитозин диоксигеназы; tdT — терминальные дезокситидилтрансферазы; C/EBPa, Klf4 и Tfcp2l1 — белки, участвующие в активном деметилировании ДНК; MBPs — метил-цитозин-связывающие белки; HATs — гистоновые ацетилтрансферазы; HDACs — гистоновые деацетилазы; HMTs — гистоновые метилтрансферазы; HDMs — гистоновые деметилазы; DUBs — деубиквитинирующие ферменты; HCTs — гистон-кротонилтрансферазы; PPIases — пептидил-пролил-цис/транс-изомеразы; PARPs — поли(АДФ-рибоза)полимеразы; tRNAs — транспортные РНК; rRNAs — рибосомные РНК; small RNAs — малые нкРНК; lncRNAs — длинные нкРНК; HIRA (histone cell cycle regulator), DAXX (death-associated protein), NAP (nucleosome assembly protein), CAF1 (chromatin assembly factor-1) и ASF1 (anti-silencing function 1A factor) — гистновые шапероны; ISWI (imitation switch), SWI/SNF (switch/sucrose non-fermentable), INO80 (inositol), NuRD/Mi2/CHD (chromodomain helicase DNA-binding) — комплексы ремоделирования хроматина; TADs — топологически ассоциированные домены; LLPS — фазовое разделение «жидкость–жидкость»; satDNAs — сателлитные ДНК; SARs (scaffold-attachment regions) и MARs (matrix-associated regions) — последовательности ДНК прикрепления к ядерному матриксу; SATB1 (special AT-rich sequence-binding protein-1) — белок, специфически связывающийся с АТ-богатыми последовательностями ДНК; CTCF — CCCTC-связывающий фактор.

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3. Рис. 2. Эпигенетические изменения и их роль при посттравматическом стрессовом расстройстве (ПТСР). ↑ (↓) 5mC (5hmC) — повышение (снижение) количества 5-метилцитозина (5-гидроксиметилцитозина); H3, H4 — гистоны; XX, XY — самка, самец; MGEs — мобильные генетические элементы; VNTRs — минисателлитные ДНК с изменяющимся числом тандемных повторов; LINEs — длинные диспергированные элементы генома.

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4. Рис. 3. Основные группы соединений и немедикаментозных подходов, которые можно применять при эпигенетической терапии посттравматического стрессового расстройства. 5mC — 5-метилцитозин; 5hmC — 5-гидроксиметилцитозин; нкРНК — некодирующие РНК; MGEs — мобильные генетические элементы; ↑, ↓ — повышение, понижение уровня вещества (модификаций) или вероятность события (процесса); inh — ингибиторы DNMTs — ДНК-метилтрансфераз, TETs — белки из семейства «транслокаций десять-одиннадцать» метилцитозин диоксигеназы, HATs — гистоновых ацетилтрансфераз, HDACs — гистоновых деацетилаз, HMTs — гистоновых метилтрансфераз, HDMs — гистоновых деметилаз; ACET+ — диета, обогащенная ацетатом; methDNA — метилированная ДНК; SAM — S-аденозил-метионин; SAH — S-аденозил-L-гомоцистеин; ssOligo — однонитевые олигонуклеотиды.

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