H3K4me3 mediates uterine leiomyoma pathogenesis via neuronal processes, synapsis components, proliferation, and Wnt/β-catenin and TGF-β pathways

Reproductive Biology and Endocrinology

Research

James M. Flanagan¹  Elena Juarez-Barber²  Amparo Faus²  Hortensia Ferrero²  Marina Segura-Benítez³  María Cristina Carbajo-García⁴  Antonio Pellicer⁵  Alexandra Trelis⁶  Javier Monleón⁶  Greta Carmona-Antoñanzas⁷ 

[1] Department of Surgery and Cancer, Imperial College London, London, UK;Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026, Valencia, Spain;Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026, Valencia, Spain;Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain;Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026, Valencia, Spain;Departamento de Pediatría, Obstetricia y Ginecología, Universidad de Valencia, Valencia, Spain;Department of Surgery and Cancer, Imperial College London, London, UK;Fundación IVI, Instituto de Investigación Sanitaria La Fe, 46026, Valencia, Spain;IVIRMA Rome, Rome, Italy;Hospital Universitario y Politécnico La Fe, Valencia, Spain;Instituto de Medicina Genómica, Valencia, Spain;

关键词: Histone modification;    H3K4me3;    Gene expression;    Proliferation;    Wnt/β-catenin;    Uterine leiomyoma;   

DOI  :  10.1186/s12958-023-01060-2

 received in 2022-08-04, accepted in 2023-01-11,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundUterine leiomyomas (UL) are the most common benign tumor in women of reproductive age. Their pathology remains unclear, which hampers the development of safe and effective treatments. Raising evidence suggests epigenetics as a main mechanism involved in tumor development. Histone modification is a key component in the epigenetic regulation of gene expression. Specifically, the histone mark H3K4me3, which promotes gene expression, is altered in many tumors. In this study, we aimed to identify if the histone modification H3K4me3 regulates the expression of genes involved in uterine leiomyoma pathogenesis.MethodsProspective study integrating RNA-seq (n = 48) and H3K4me3 CHIP-seq (n = 19) data of uterine leiomyomas versus their adjacent myometrium. Differentially expressed genes (FDR < 0.01, log2FC > 1 or < − 1) were selected following DESeq2, edgeR, and limma analysis. Their differential methylation and functional enrichment (FDR < 0.05) were respectively analyzed with limma and ShinyGO.ResultsCHIP-seq data showed a global suppression of H3K4me3 in uterine leiomyomas versus their adjacent myometrial tissue (p-value< 2.2e-16). Integrating CHIP-seq and RNA-seq data highlighted that transcription of 696/922 uterine leiomyoma-related differentially expressed genes (DEG) (FDR < 0.01, log2FC > 1 or < − 1) was epigenetically mediated by H3K4me3. Further, 50 genes were differentially trimethylated (FDR < 0.05), including 33 hypertrimethylated/upregulated, and 17 hypotrimethylated/downregulated genes. Functional enrichment analysis of the latter showed dysregulation of neuron-related processes and synapsis-related cellular components in uterine leiomyomas, and a literature review study of these DEG found additional implications with tumorigenesis (i.e. aberrant proliferation, invasion, and dysregulation of Wnt/β-catenin, and TGF-β pathways). Finally, SATB2, DCX, SHOX2, ST8SIA2, CAPN6, and NPTX2 proto-oncogenes were identified among the hypertrimethylated/upregulated DEG, while KRT19, ABCA8, and HOXB4 tumor suppressor genes were identified among hypotrimethylated/downregulated DEG.ConclusionsH3K4me3 instabilities alter the expression of oncogenes and tumor suppressor genes, inducing aberrant proliferation, and dysregulated Wnt/β-catenin, and TGF-β pathways, that ultimately promote uterine leiomyoma progression. The reversal of these histone modifications may be a promising new therapeutic alternative for uterine leiomyoma patients.

【 授权许可】

CC BY   
© The Author(s) 2023

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