Исследование роли коактиватора транскрипции SAYP в активации DHR3-зависимой транскрипции генов у Drosophila melanogaster тема диссертации и автореферата по ВАК РФ 03.01.03, кандидат биологических наук Кузьмина, Юлия Леонидовна

• Кузьмина, Юлия Леонидовна
• кандидат биологических наук
• 2012

Оглавление диссертации кандидат биологических наук Кузьмина, Юлия Леонидовна

СОДЕРЖАНИЕ

СОДЕРЖАНИЕ

СПИСОК СОКРАЩЕНИЙ

ВВЕДЕНИЕ

ОБЗОР ЛИТЕРАТУРЫ

Глава 1. Факторы транскрипции

Транскрипционный аппарат эукариот

РНК-полимераза II

Классификация факторов транскрипции

Общие факторы транскрипции GTFs

Активаторы и репрессоры

Ядерные рецепторы

Корегуляторы

Глава 2. Участие хроматина в транскрипции

Посттрансляционные модификации гистонов. Гистоновый код

Механизмы регуляции транскрипции на уровне хроматина

Ремоделинг хроматина и гистоновый обмен

Вариативные гистоны

Нуклеосома как транскрипционный барьер

Глава 3. Транскрипционный цикл эукариот

Инициация транскрипции

Пауза РНК-полимеразы на промоторе

Переход от абортивной к продуктивной инициации транскрипции

Факторы и события, влияющие на элонгацию

Терминация транскрипции

Генное выпетливание

ОБЪЕКТ И ЗАДАЧИ ИССЛЕДОВАНИЯ

МАТЕРИАЛЫ И МЕТОДЫ

МАТЕРИАЛЫ

Ферменты, киты и реактивы

Векторные конструкции

Праймеры

Штаммы Е. coli

Культуры эукариотических клеток

Среды для культивирования

Линии мух

Антитела

Програмное обеспечение. Базы данных

МЕТОДЫ

Работа с ДНК

Работа с РНК

Работа с белками

Работа с S2 клетками

РЕЗУЛЬТАТЫ

Получение политональных антител к белку ИНЯЗ

Белок ИНЯЗ взаимодействует с компонентом высокомолекулярного комплекса ВТПу

коактиватором БАУР на стадии эмбриона и куколки

Гены е(у)3 и ОНЯЗ имеют схожий профиль экспрессии в ходе развития ОгояорИПа

Гены е(у)3 и ОНЯЗ взаимодействуют в ходе развития Пго$орЫ1а

ВНИЗ связывается с промоторами БАУР-зависимых генов на стадии средней куколки82

Модельная система активации ИНЯЗ в культуре клеток Б2

ВНИЗ и Б АУР совместно активируют экспрессию генов СОИ395 и Сур12а5 в культуре

клеток

Б АУР рекрутируется на промотор БНЯЗ -зависимого гена /&-// после активации

экспрессии ИНЯЗ в составе суперкомплекса ВТПу

ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ

Модель участия БАУР ОНЯЗ-зависимой транскрипции

ВЫВОДЫ

СПИСОК ЛИТЕРАТУРЫ

Введение диссертации (часть автореферата) на тему «Исследование роли коактиватора транскрипции SAYP в активации DHR3-зависимой транскрипции генов у Drosophila melanogaster»

Сложная система клеточной коммуникации обеспечивает способность клетки получать информацию из ее окружения и изменять свой метаболизм в ответ на поступающие сигналы. Возможность клеток реагировать на изменения окружающей среды является основой развития, репарации тканей, иммунитета и системы поддержания гомеостаза в целом. Нарушения клеточной сигнализации могут приводить к различным серьезным заболеваниям. Понимание механизмов передачи сигнала внутри клетки необходимы для разработки методов лечения различных заболеваний.

Передача сигнала в клетке осуществляется обычно через каскад биохимических реакций. В случае, когда конечным звеном каскада являются транскрипционные факторы, происходит изменение профиля экспрессии определенных генов-мишеней. Изменение профиля экспрессии влечет за собой изменения в метаболизме, строении и функциях клетки и определяет ее дальнейшую судьбу. В данном процессе одну из ключевых ролей играют различные транскрипционные факторы.

Транскрипционный аппарат клетки необычайно сложно устроен и данные о механизме его работы постоянно дополняются. Основной фермент транскрипционного аппарата - ДНК-зависимая РНК-полимераза. Для эукариотических клеток характерна специализация РНК полимераз, то есть транскрипция определенного типа генов осуществляется специальной РНК-полимеразой. Так, экспрессию генов, кодирующих мРНК, контролирует РНК-полимераза II. Несмотря на свое сложное строение, она не способна самостоятельно инициировать транскрипцию. Для этого ей необходимы многочисленные вспомогательные факторы.

На данный момент выделяют три условные группы факторов транскрипции: общие факторы транскрипции, необходимые для экспрессии большинства генов, специфические факторы транскрипции (активаторы и репрессоры) и так называемые корегуляторы

(коактиваторы и корепрессоры). Последние осуществляют связь между специфическими и общими факторами транскрипции, а также изменяют структуру хроматина. Традиционно биологические исследования сфокусированы на изучении отдельных частей транскрипционного аппарата. Знания об устройстве аппарата транскрипции важны как в теоретическом плане, так и для изучения патологий, связанных с нарушениями в его работе.

Основной целью данной работы являлось изучение роли транскрипционного фактора Б АУР как коактиватора транскрипции для ядерного рецептора БНЮ у Э. твЫпо^азгег. Транскрипционный коактиватор 8АУР и ядерный рецептор БНЯЗ незаменимы в развитии, консервативны в эволюции и имеют гомологов в протеоме человека. Мутации данных белков их гомологов вызывают тяжелые нарушения в развитии как В. те1апо$а$1ег, так и человека. Гомолог 8АУР, белок РНИО человека, также важен в контроле пролиферации клеток.

Для изучения взаимодействия данных белков были использованы разнообразные физико-химические методы работы с ДНК, РНК, белками, методы биоинформатики. В работе показано взаимодействие коактиватора БАУР с ядерным рецептором БНЯЗ как биохимических, так и в генетических экспериментах. Показано совместное участие активатора БНЯЗ и коактиватора Б АУР в активации транскрипции нескольких генов. Также были получены новые данные о работе экдизонового каскада, предложен механизм действия ядерного рецептора БНИ-З-

Ввиду того, что транскрипционный коактиватор БАУР и ядерный рецептор ОНЯЗ имеют гомологов в протеоме человека, изучение их функций на примере модельного объекта I). melanogaster поможет понять, как их гомологи функционируют в организме человека. Исследования в области изучения взаимодействия данных белков могут иметь

большое фундаментальное значение, а также практическое применение в медицине, фармакологии, биотехнологии и селекции.

Заключение диссертации по теме «Молекулярная биология», Кузьмина, Юлия Леонидовна

выводы

1. Установлено, что в организме D. melanogaster ядерный рецептор DHR3 ассоциирован с коактиваторным суперкомплексом BTFly посредством взаимодействия с SAYP.

2. Для генов DHR3 и е(у)3, кодирующих DHR3 и SAYP, показано генетическое взаимодействие и коэкспрессия в развитии D. melanogaster.

3. Найдены новые гены-мишени DHR3. Показано влияние DHR3 на транскрипцию ранее неизвестных для него генов-мишеней, которые контролируются также SAYP.

4. Показано, что DHR3 и SAYP привлекаются на промоторы генов-мишеней при активации экдизонового каскада в культуре клеток S2 D. melanogaster.

5. Показано участие SAYP в DHR3-3aBHCHMoft транскрипции в условиях активации экдизонового каскада в культуре клеток S2 D. melanogaster.

6. Установлено, что SAYP участвует в привлечении на промотор DHR3-зависимого гена/fe-// компонентов коактиваторного суперкомплекса BTFly и РНК-полимеразы II, формируя преинициаторный комплекс перед началом транскрипции.

7. Разработана система активации части генов экдизонового каскада в культуре клеток S2 D. melanogaster.

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