References

vavilov

Вавиловский журнал генетики и селекции

Vavilov Journal of Genetics and Breeding

2500-3259

Institute of Cytology and Genetics of Siberian Branch of the RAS

10.18699/VJGB-22-37

vavilov-3365

Research Article

БИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУ

MEDICAL GENETICS

Молекулярно-генетические особенности патогенеза идиопатического легочного фиброза

Molecular genetics of idiopathic pulmonary fibrosis

https://orcid.org/0000-0002-4091-382X

Мустафин

Р. Н.

Mustafin

R. N.

Уфа

Ufa

ruji79@mail.ru

Башкирский государственный медицинский университетРоссияBashkir State Medical UniversityRussian Federation

2022

04062022

263308318

2022

Мустафин Р.Н.

Mustafin R.N.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://vavilov.elpub.ru/jour/article/view/3365

Идиопатический легочный фиброз – тяжелая прогрессирующая интерстициальная болезнь л ких с распространенностью 2–29 случаев на 100 000 человек населения в мире. Значимым фактором риска заболевания является старение, механизмы развития которого задействованы в патогенезе идиопатического легочного фиброза. К ним относятся истощение теломер, геномная нестабильность, дисфункция митохондрий и потеря протеостаза. Важную роль в развитии идиопатического легочного фиброза играют также эпителиально-мезенхимальный переход, активация TGF-β и снижение экспрессии сиртуина SIRT7. Молекулярно-генетические исследования показали, что в патогенезе идиопатического легочного фиброза имеют значение мутации и полиморфизмы в генах муцина (MUC5B), в генах, ответственных за целостность теломер (TERC, TERT, TINF2, DKC1, RTEL1, PARN), генов сурфактанта (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2) и иммунной системы (IL1RN, TOLLIP), а также гаплотипы генов HLA (DRB1*15:01, DQB1*06:02). Перспективно изучение влияния на развитие болезни обратимых эпигенетических факторов, которые могут быть скорректированы таргетной терапией. Среди них с идиопатическим легочным фиброзом ассоциированы специфические микроРНК и длинные некодирующие РНК. Сделано предположение, что драйверным событием для идиопатического легочного фиброза служит дисрегуляция транспозонов, которые являются ключевыми источниками некодирующих РНК и влияют на механизмы старения. Это обусловлено тем, что при патологической активации транспозонов происходит нарушение регуляции генов, в эпигенетическом управлении которых участвуют происходящие от этих транспозонов микроРНК (в связи с комплементарностью нуклеотидных последовательностей). Анализ базы данных MDTE (miRNAs derived from Transposable Elements) позволил выявить 12 различных микроРНК, гены которых в эволюции возникли от транспозонов и ассоциированы с идиопатическим легочным фиброзом (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). Описаны взаимосвязи мобильных элементов с TGF-β, сиртуинами и теломерами, дисфункция которых вовлечена в патогенез идиопатического легочного фиброза. Новые данные об эпигенетических механизмах развития патологии могут стать основой для улучшения результатов таргетной терапии болезни с использованием в качестве мишени некодирующих РНК.

Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease with a prevalence of 2 to 29 per 100,000 of the world’s population. Aging is a significant risk factor for IPF, and the mechanisms of aging (telomere depletion, genomic instability, mitochondrial dysfunction, loss of proteostasis) are involved in the pathogenesis of IPF. The pathogenesis of IPF consists of TGF-β activation, epithelial-mesenchymal transition, and SIRT7 expression decrease. Genetic studies have shown a role of mutations and polymorphisms in mucin genes (MUC5B), in the genes responsible for the integrity of telomeres (TERC, TERC, TINF2, DKC1, RTEL1, PARN), in surfactant-related genes (SFTPC, SFTPCA, SFTPA2, ABCA3, SP-A2), immune system genes (IL1RN, TOLLIP), and haplotypes of HLA genes (DRB1*15:01, DQB1*06:02) in IPF pathogenesis. The investigation of the influence of reversible epigenetic factors on the development of the disease, which can be corrected by targeted therapy, shows promise. Among them, an association of a number of specific microRNAs and long noncoding RNAs was revealed with IPF. Therefore, dysregulation of transposons, which serve as key sources of noncoding RNA and affect mechanisms of aging, may serve as a driver for IPF development. This is due to the fact that pathological activation of transposons leads to violation of the regulation of genes, in the epigenetic control of which microRNA originating from these transposons are involved (due to the complementarity of nucleotide sequences). Analysis of the MDTE database (miRNAs derived from Transposable Elements) allowed the detection of 12 different miRNAs derived in evolution from transposons and associated with IPF (miR-31, miR-302, miR-326, miR-335, miR-340, miR-374, miR-487, miR-493, miR-495, miR-630, miR-708, miR-1343). We described the relationship of transposons with TGF-β, sirtuins and telomeres, dysfunction of which is involved in the pathogenesis of IPF. New data on IPF epigenetic mechanisms can become the basis for improving results of targeted therapy of the disease using noncoding RNAs.

идиопатический легочный фиброзиммунная системамикроРНКтеломерытранспозоныэпигенетические факторы

idiopathic pulmonary fibrosisimmune systemmicroRNAtelomerestransposonsepigenetic factors

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