Эволюция и механизмы регуляции экспрессии повторяющихся генов в геноме Drosophila

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Биологические науки
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1. Установлены эволюционные взаимоотношения семейства родственных генов, участвующих в сперматогенезе. Впервые показано эволюционное происхождение в геноме протяженных участков конститутивного гетерохроматина дрозофилы в результате амплификации функционального эухроматического гена. Обнаружен новый функциональный ген, кодирующий семенник-специфичную регуляторную субъединицу казеин-киназы 2 (jBCK2tes). Являясь функциональной ретрокопией гена /ЗСК2, этот ген, в свою очередь, является предком семейств тандемно-повторяющихся генов X и Y хромосом (Ste и Su (Ste)).

2. Показано существование в одном геноме нескольких структурно-функциональных вариантов ретротранспозона 1731. Исследованы структурные варианты регуляторной и кодирующей областей ретротранспозона 1731. Выявлено наличие двух типов копий, различающихся изменениями в области трансляционного сдвига рамки считывания, а также исследован полиморфизм регуляторной области длинного концевого повтора. Показано, что недавно возникшие копии этого элемента, обладающие широким спектром экспрессии, вытеснили более древний вариант.

3. Гены, кодирующие компоненты РНК интерференции, участвуют в контроле экспрессии и частоты перемещений ретротранспозонов в герминальных тканях Показано, что компоненты, РНКи подавляют, экспрессию широкого спектра ретротранспозонов в герминальных клетках яичников. Белок Piwi участвует в регуляции экспрессии и частоты транспозиций ретротранспозонов в семенниках.

4. Экспрессия и частота перемещений теломерных ретротранспозонов в яичниках дрозофилы регулируется с помощью коротких РНК, т.о., система РНКи осуществляет негативную регуляцию длины теломер у дрозофилы.

5. Экспрессия репортерных генов, находящихся под контролем промотора теломерного ретротранспозона НеТ-А, регулируется по механизму РНКи в герминальных тканях самок дрозофилы независимо от положения репортерных конструкций в геноме.

6. Ретротранспозон TAHRE способен перемещаться на конец хромосомы, и, следовательно, этот элемент является полноправным участником поддержания теломер у дрозофилы. Установлено, что промотор ретротранспозона TAHRE, так же как у НеТ-А, находится в 3'-конце нетранслируемой области данного элемента.

7. Изучено происхождение и биогенез антисмысловых транскриптов. теломерных ретротранспозонов, необходимых для образования коротких РНК. Картирован антисмысловой промотор теломерного ретротранспозона НеТ-А. Показано, что некодирующие антисмысловые транскрипты процессируются и полиаденилируются. Антисмысловые транскрипты теломерных ретроэлементов НеТ-А и TART являются мишенями РНКи, так же как и смысловые транскрипты, и накапливаются в ядрах терминальных клеток у мутантов по генам РНКи в области теломеры, что указывает на транскрипционный механизм сайленсинга теломерных повторов.

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Содержание

Список сокращений

Введение б

Обзор литературы

Общие принципы организации и функционирования гетеророматина

Структура п эволюция гетерохроматиновых кластеров генов половых хромосом у Drosophila

Ретротранспозоны и их роль в эволюции генома-хозяина

Система РНК-интерференции и ее роль в регуляции экспрессии ретротранспозонов

Общие принципы работы системы РНК-интерференции

Роль РНК-интерференции в регуляции экспрессии ретротранспозонов

Механизм образования piPHK 23 Функции теломер 27 Принципы организации теломер, образуемых теломеразой

Принципы оранизации теломер Drosophila

Структура теломер Drosophila 33 Клтровапие теломер Drosophila

Хроматин, связанный с субтеломерными последовательностями

Модификации гистонов в теломерной обпасти дрозофилы 43 Структура хроматина в области повторов HeT-A/TART/TAHRE и регуляция транскрипции теломерных ретротранспозонов Drosophila

Материалы и методы

Лабораторные линии Drosophila и линии культур клеток, использованные в работе

Выделение геномной ДНК

ПЦР на геномной ДНК. Полукличественная ПЦР на геномной ДНК

Саузерн-блот анализ.

Обратный ПЦР и детекция транспозиций mdgl

Стандартные генно-инженерные методики

Выделение РНК

Полуколичественный RT-PCR

РНК in situ гибридизация

Нозерн-блот анализ тотальной РНК Drosophila melanogaster

Нозерн-блот анализ коротких РНК Drosophila melanogaster

Сочетание методов РНК, ДНК FISH и иммуноокрашпвания

5' RACE (rapid amplification of cDNA ends) анализ 62 Клонирование промоторных областей ретротранспозонов НсТ-А и ТАНЯЕаля измерения их активности 63 Получение конструкций для исследования механизма трансляционного сдвига (frameshifting) ретротранспозона

Трансфекция культуры клеток Drosuphila и количественное определение активности галактозидазы

Вестерн-анализ

Иммуноирецинитация и гель-фильтрация

Получение эксирессирующих конструкций и конструкций для Р-элементной трансформации

Тесты на активность СК2 67 Окрашивание тканей на Р-галактозидазу. Количественное определение активности Р-галактоэидазы

Результаты

Эволюционные связи в семействе генов, роде i венных регуляторной субъединице казеин киназы 2 (СК2) Drosophila

Обнаружение гена SSL (j3CK2tes) pCK2tes выполняет функции регуляторной субъединицы СК2 в семенниках

Эволюция структурных вариантов ретро гранспозона Drosophila

Структурные варианты кодирующей области ретротранспозона

Структурные варианты ДКГ1 ретротранспозона

Роль системы РНК-сайленсннга в регуляции активности широкого спектра ретротранспозонов в терминальных тканях Drosophila

Деренрессия ретротранспозонов в яичниках Drosophila у мутантов piPHK пути

Белок Piwi контролирует частоту транспозиций ретротранспозона в герминальных тканях самцов

Роль системы РНК-сайленсинга в регуляции активности теломерных ретроэлементов Drosophila

Экспрессия теломерных ретротранспозонов НеТ-А, TART и TAHRE в герминальных тканях регулируется с помощью piPHK

Увеличение частоты транспозиций теломерных элементов на конец хромосомы на фоне мутаций, но генам spn-E и aub

Мутации генов spn-E и aub в гетерозиготном состоянии вызывают активные транспозиции на конец хромосомы ретротранспозона TART

Активные транспозиции ретротранспозона НеТ-А к концу хромосомы происходят на фоне мутации гена spn-E в гомозиготном состоянии

Характеристика теломерного ретротранспозона TAHRE

Ретротранспозон TAHRE участвует в поддержании теломер Drosophila

Ретротранспозон TAHRE присутствует в геномах разных линий D. melanogaster и других видов Drosophila область TAHRE обладает промоторной активностью

Экспрессия репортерных генов, находящихся под промотором ретротранспозона НеТ-А, находится под контролем piPHK пути

Свойства антисмысловой экспрессии теломерных ретротранспозонов

Картирование антисмыслового промотора НеТ-А

Анализ ашписмысловой экспрессии теломерных ретротранспозонов

Обсуждение

Эволюция повторяющихся последовательностей генома Drosophila

Роль РНКи в регуляции экспрессии ретротранспозонов у Drosophila

Выводы

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