Integrative analysis of the DNA methylome and transcriptome in uterine leiomyoma shows altered regulation of genes involved in metabolism, proliferation, extracellular matrix and vesicles.

Fecha de publicación: 26/04/2022 Fecha Ahead of Print: 26/04/2022

Autores de IIS La Fe

Maria Cristina Carbajo García

Autor
Ana Corachán García

Autor
Elena Juarez Barber

Autor
Javier Monleón Sancho

Autor
Vicente Payá Amate

Autor
Alexandra Trells Blanes

Autor
Antonio Pellicer Martínez

Autor
Hortensia Ferrero Chafer

Autor

Participantes ajenos a IIS La Fe

Quinonero, Alicia

Grupos

Biología Reproductiva y Bioingeniería en Reproducción Humana

Leader

Nicolás Garrido Puchalt
Medicina Reproductiva

Investigador Principal

José Morales Roselló

Abstract

Uterine leiomyomas (ULs) are the most common benign tumors in women of reproductive age. Despite the high prevalence, tumor pathology remains unclear, which hampers the development of safe and effective treatments. Epigenetic mechanisms appear to be involved in UL development, particularly via DNA methylation that regulates gene expression. We aimed to determine the relationship between DNA methylation and gene expression in UL compared with adjacent myometrium (MM) to identify molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, and a different global transcriptome profile. Integration of DNA methylation and whole-transcriptome RNA-sequencing data identified 93 genes regulated by methylation, with 22 hypomethylated/upregulated and 71 hypermethylated/downregulated. Functional enrichment analysis showed dysregulated biological processes and molecular functions involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation, as well as pathways related to uterine biology and cancer. Cellular components such as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation/upregulation of oncogenes (PRL, ATP8B4, CEMIP, ZPMS2-AS1, RIMS2, TFAP2C) and hypermethylation/downregulation of tumor suppressor genes (EFEMP1, FBLN2, ARHGAP10, HTATIP2), which are related to proliferation, invasion, altered metabolism, deposition of extracellular matrix, and Wnt/beta-catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, inhibition of DNA methyltransferases by 5-aza-2'-deoxycitidine increased the expression of hypermethylated/downregulated genes in UL cells in vitro. In conclusion, gene regulation by DNA methylation is implicated in UL pathogenesis, and reversion of this methylation could offer a therapeutic option for UL. (c) 2022 The Pathological Society of Great Britain and Ireland.

Datos de la publicación

ISSN/ISSNe:: 0022-3417, 1096-9896
Tipo:: Article
Páginas:: 663-673
DOI:: 10.1002/path.5920
Factor de Impacto:: 2,537 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Filiaciones

Carbajo-Garcia, Maria Cristina:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain
Corachan, Ana:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain
Juarez-Barber, Elena:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
Monleon, Javier:: Hospital Universitario y Politécnico La Fe, Valencia, Spain
Paya, Vicente:: Hospital Universitario y Politécnico La Fe, Valencia, Spain
Trelis, Alexandra:: Hospital Universitario y Politécnico La Fe, Valencia, Spain
Quinonero, Alicia:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
Pellicer, Antonio:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain

IVIRMA Rome, Rome, Italy
Ferrero, Hortensia:: Instituto de Investigación. Fundación IVI, Instituto de Investigación Sanitaria La Fe, Valencia, Spain