vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-24-85vavilov-4350Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSТранскрипционный фактор TCF4: структура, функции и ассоциированные заболеванияTranscription factor TCF4: structure, function, and associated diseaseshttps://orcid.org/0000-0003-3839-3543СавченкоР. Р.SavchenkoR. R.

Томск

Tomsk

renata.savchenko@medgenetics.ruhttps://orcid.org/0000-0002-2491-3141СкрябинН. А.SkryabinN. A.

Томск

Tomsk

Научно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наукРоссияResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesRussian Federation202422112024287770779Copyright © Савченко Р.Р., Скрябин Н.А., 20242024Савченко Р.Р., Скрябин Н.А.Savchenko R.R., Skryabin N.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/4350

На сегодняшний день имеются ограниченные знания об основных характеристиках генов человека, их структуре, функции и механизмах регуляции экспрессии. Биологическая роль около 20 % белковых продуктов генов до сих пор не установлена, а молекулярные функции известной части протеома остаются недостаточно изученными. Данное обстоятельство ограничивает прогресс как фундаментальных, так и прикладных биологических и медицинских наук, в особенности в случае терапии наследственных болезней, патогенез которых обусловлен наличием вариантов в нуклеотидной последовательности отдельных генов. В связи с этим возрастает необходимость проведения исследований, направленных на изучение функций генов, а также молекулярных патогенетических путей, связанных с развитием моногенных заболеваний. Наша статья посвящена гену TCF4, кодирующему широко экспрессируемый фактор транскрипции, важный для развития и функционирования нервной системы. К настоящему времени установлено, что патогенные варианты в этом гене приводят к развитию редкого генетического заболевания, известного как синдром Питта–Хопкинса, а полиморфные варианты в TCF4 ассоциированы с рядом социально значимых заболеваний, представленных различными психическими расстройствами. Молекулярные механизмы патогенеза подобных состояний по-прежнему остаются неизученными, а знания о вышестоящей регуляции TCF4 и его нижестоящих генах-мишенях ограничены. Сложность структурной организации и особенности регуляции экспрессии гена обеспечивают многообразие изоформ TCF4, что затрудняет понимание молекулярных функций белка. В обзоре рассмотрены известные данные о структуре и функциях фактора транскрипции TCF4. Обсуждаются потенциальные гены-мишени и возможные патогенетические механизмы, обусловленные потерей функции этого белка, выявленные в исследованиях на животных и клеточных моделях синдрома Питта–Хопкинса. Рассмотрены преимущества и ограничения потенциальных стратегий терапии указанного синдрома, основанные на компенсации дозы TCF4 или воздействии на молекулярные мишени изучаемого транскрипционного фактора.

Our understanding of human genes - particularly their structure, functions, and regulatory mechanisms - is still limited. The biological role of approximately 20 % of human proteins has not been established yet, and the molecular functions of the known part of the proteome remain poorly understood. This hinders progress in basic and applied biological and medical sciences, especially in treating hereditary diseases, which are caused by mutations and polymorphic variants in individual genes. Therefore, it is crucial to comprehend the mechanisms of protein functioning to address this problem. This further emphasizes the importance of investigating gene functions and molecular pathogenetic pathways associated with single-gene inherited diseases. This review focuses on the TCF4 gene that encodes a transcription factor crucial for nervous system development and functioning. Pathogenic variants in this gene have been linked to a rare genetic disorder, Pitt–Hopkins syndrome, and TCF4 polymorphic variants are associated with several socially significant diseases, including various psychiatric disorders. The pathogenetic mechanisms of these conditions remain unexplored, and the knowledge about TCF4 upregulation and its target genes is limited. TCF4 can be expressed in various isoforms due to the complex structure and regulation of its gene, which complicates the investigation of the protein’s functions. Here, we consider the structure and functions of the TCF4 transcription factor. We discuss its potential target genes and the possible loss-of-function pathogenetic mechanisms identified in animal and cellular models of Pitt–Hopkins syndrome. The review also examines the advantages and limitations of potential therapies for Pitt–Hopkins syndrome that are based on TCF4 dosage compensation or altering the activity of TCF4 target genes.

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The authors declare that there are no conflicts of interest present.