Образовательная программа «6D060722- молекулярная и клеточная биология»

Исследованные сайты генов PTPN12, MSH6, ZEB1 показывает стабильную консервативность сайтов микроРНК среди млекопитающих и позвоночных, что свидетельствует о значимости данных сайтов в регуляции генов мишеней.

Полученные результаты свидетельствуют, что сайты связывания с высокой комплементарностью, локализованные в кодирующей области мРНК, высоко консервативны среди позвоночных.

В результате исследования филогенетической консервативности сайтов связывания микроРНК c мРНК были опубликованы ряд публикаций [348-350].

ЗАКЛЮЧЕНИЕ
Настоящая диссертация посвящена идентификации важных генов и микроРНК, которые участвуют в развитии рака толстой кишки. Для этого были созданы база данных по генам с наличием мутаций при этом заболевании и база данных по микроРНК, у которых обнаружено изменение экспрессии при РТК. Из базы отобраны 54 белок кодирующих гена, которые имеют важную функциональную роль и наибольшее количество исследований и на их основе проведен поиск микроРНК с помощью программы RNAhybrid, которые регулируют эти гены. Для этого была разработана методика отбора сайтов микроРНК на основе введенного нами параметра score (ΔG/ΔG_m). В результате исследования были идентифицированы 120 микроРНК, которые могут быть ключевыми молекулами в регуляции 47 генов мишеней. Найденные сайты микроРНК имеют почти полную комплементарность и ранее не описаны в других исследованиях. Как показано в работе Brennecke с соавторами (таблица 6) [146] многие не канонические сайты могут иметь очень высокую регуляторную эффективность. Большинство описанных нами сайтов относятся к неканоническим сайтам, так как имеют Г:У пары и неспаренные нуклеотиды в 5'конце микроРНК. При сравнении сайтов предсказанных с помощью программ RNAhybrid, TargetScan и miRanda было установлено, что программа TargetScan предсказывает только канонические сайты связывания микроРНК и не находит всех комплементарных пар в канонических сайтах с высокой комплементарностью. Программа miRanda предсказывает все сайты, найденные с помощью программы RNAhybrid, но большинство этих сайтов не доступны на он-лайн резурсе microrna.org, которая представляет сайты предложенные программой miRanda. Программы TargetScan и miRanda широко используются среди исследователей для поиска значимых микроРНК в регуляции определенных генов. В связи с этим сайты с высокой комплементарностью описанные в нашей работе еще не изучены. Для подтверждения сайтов связывания микроРНК исследована филогенетическая консервативность сайтов микроРНК. Установлено, что сайты в 3'нетранслируемой области имеют низкую консервативность, а сайты, расположенные в кодирующей последовательности мРНК, высоко консервативны среди позвоночных. Мы надеемся, что описанные сайты будут основой для разработки молекулярных маркеров для диагностики и разработки лекарственных средств для лечения рака.

На основе полученных результатов были сделаны следующие выводы:

1. Из 142 генов кандидатов, ответственных за развитие рака толстой кишки, выявлено 54 гена, имеющих ключевую роль в развитии рака, и создана база данных по этим генам.

2. Найдены 185 потенциальных сайта взаимодействия для 120 межгенных микроРНК, которые могут регулировать 47 из 54 генов, ответственных за развитие рака толстой кишки. Все описанные сайты имеют высокий уровень комплементарности.

3. Сайты взаимодействия микроРНК расположены во всех участках мРНК. Установлено, что 23%, 42%, 35% сайтов находятся в 5'UTR, CDS и 3'UTR мРНК, а средняя плотность сайтов связывания микроРНК в 5'UTR в четыре раза выше, чем в CDS и 3'UTR.

4. Установлены три вида сайтов связывания микроРНК с мРНК в зависимости от вклада микроРНК в энергию гибридизации: 5'-доминантный, 3'-доминантный сайты и сайты с центральным доминированием. Неспаренные нуклеотиды во вторичной структуре мРНК служат основой для образования связи между микроРНК и мРНК.

5. Модифицированная программа RNAhybrid позволяет находить большее число достоверных сайтов связывания и лучше определять характеристики взаимодействия микроРНК с мРНК.

6. Сайты взаимодействия микроРНК расположенные в 3'UTR имеют низкую филогенетическую консервативность, а сайты в CDS имеют высокую консервативность.

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