Молекулярная биология, 2022, T. 56, № 3, стр. 355-390

Эффект положения гена: роль локального окружения в регуляции активности генов

Л. В. Болдырева a*, Е. Н. Андреева a, А. В. Пиндюрин a

a Институт молекулярной и клеточной биологии Сибирского отделения Российской академии наук
630090 Новосибирск, Россия

* E-mail: asd@mcb.nsc.ru

Поступила в редакцию 14.07.2021
После доработки 25.08.2021
Принята к публикации 25.08.2021

Аннотация

При перемещении гена в результате хромосомных перестроек или при встраивании идентичных генетических конструкций в разные районы генома наблюдается так называемый эффект положения гена – явление, при котором уровень экспрессии одного и того же гена существенно зависит от его положения в геноме. Геном эукариот имеет доменную организацию, а активность генов в пределах таких доменов определяется не столько нуклеотидной последовательностью гена, сколько структурой окружающего хроматина, т.е. эпигенетически. Хроматин представляет собой сложный комплекс ДНК, РНК и ассоциированных с ними структурных и регуляторных белков. Эпигенетический статус хроматина определяется целым рядом факторов: временем репликации данного участка генома, регуляторными мотивами ДНК, контактами с внутренней ядерной оболочкой (ламиной) и другими районами хромосом (топологически ассоциированные домены). Эффект положения гена заключается в изменении его эпигенетического состояния и является уникальным инструментом для исследования молекулярных и биохимических процессов. Понимание молекулярных механизмов эффекта положения гена у человека имеет важное значение в клинической сфере, в частности, для выявления и лечения ретровирусных инфекций, поскольку локальный состав хроматина может определять, например, переход в латентное/активное состояние такой инфекции, как ВИЧ. Кроме того, большое число нейродегенеративных заболеваний человека обусловлено эпигенетической инактивацией генов в результате экспансии коротких повторов. Наконец, для полноценного применения методов генной терапии важно владеть знаниями и подходами, которые с достаточной точностью могут обеспечивать необходимый уровень экспрессии внедряемых трансгенов.

Ключевые слова: эффект положения гена, модификаторы эффекта положения, эпигенетический статус хроматина, гистоновый код, регуляторные элементы генома, дрозофила, млекопитающие, заболевания человека

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Таблица 1. Модификаторы ЭП у дрозофилы, человека и мыши, связанные с ними сигнальные пути и заболевания человека.
 
Таблица 2. Заболевания, связанные с ЭП генов человека, возникающего в результате хромосомных перестроек.
 
Таблица 3. Заболевания человека, развивающиеся в результате ЭП, обусловленном экспансией микросателлитов (согласно [82] с модификациями).
 
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