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Frontiers in veterinary science2022; 9; 970003; doi: 10.3389/fvets.2022.970003

Metallopeptidades 2 and 9 genes epigenetically modulate equine endometrial fibrosis.

Abstract: Endometrium type I (COL1) and III (COL3) collagen accumulation, periglandular fibrosis and mare infertility characterize endometrosis. Metalloproteinase-2 (MMP-2), MMP-9 and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) are involved in collagen turnover. Since epigenetic changes may control fibroproliferative diseases, we hypothesized that epigenetic mechanisms could modulate equine endometrosis. Epigenetic changes can be reversed and therefore extremely promising for therapeutic use. Methylation pattern analysis of a particular gene zone is used to detect epigenetic changes. DNA methylation commonly mediates gene repression. Thus, this study aimed to evaluate if the transcription of some genes involved in equine endometrosis was altered with endometrial fibrosis, and if the observed changes were epigenetically modulated, through DNA methylation analysis. Endometrial biopsies collected from cyclic mares were histologically classified (Kenney and Doig category I, n = 6; category IIA, n = 6; category IIB, n = 6 and category III, n = 6). Transcription of COL1A1, COL1A2, COL3A1, MMP2, MMP9, TIMP1, and TIMP2 genes and DNA methylation pattern by pyrosequencing of COL1A1, MMP2, MMP9, TIMP1 genes were evaluated. Both MMP2 and MMP9 transcripts decreased with fibrosis, when compared with healthy endometrium (category I) (P < 0.05). TIMP1 transcripts were higher in category III, when compared to category I endometrium (P < 0.05). No differences were found for COL1A1, COL1A2, COL3A1 and TIMP2 transcripts between endometrial categories. There were higher methylation levels of (i) COL1A1 in category IIB (P < 0.05) and III (P < 0.01), when compared to category I; (ii) MMP2 in category III, when compared to category I (P < 0.001) and IIA (P < 0.05); and (iii) MMP9 in category III, when compared to category I and IIA (P < 0.05). No differences in TIMP1 methylation levels were observed between endometrial categories. The hypermethylation of MMP2 and MMP9, but not of COL1A1 genes, occurred simultaneously with a decrease in their mRNA levels, with endometrial fibrosis, suggesting that this hypermethylation is responsible for repressing their transcription. Our results show that endometrosis is epigenetically modulated by anti-fibrotic genes (MMP2 and MMP9) inhibition, rather than fibrotic genes activation and therefore, might be promising targets for therapeutic use.
Copyright © 2022 Alpoim-Moreira, Fernandes, Pimenta, Bliebernicht, Rebordão, Castelo-Branco, Szóstek-Mioduchowska, Skarzynski and Ferreira-Dias.
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Publication Date: 2022-08-12 PubMed ID: 36032279PubMed Central: PMC9412240DOI: 10.3389/fvets.2022.970003Google Scholar: Lookup
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  • Journal Article

Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research investigates the role of epigenetic changes in equine endometrosis, a disease affecting horse fertility characterized by fibrous changes in the uterine endometrium, and proposes that targeting these changes could have therapeutic potential.

Research Aim and Hypothesis

  • The study sought to explore if genes involved in equine endometrosis, a disease characterized by fibrosis (scarring) of the uterine endometrium, are under the influence of epigenetic changes.
  • The authors hypothesized that the genes important for fibrosis development, namely Collagen type I and III, matrix Metalloproteinase-2 (MMP-2) and -9 (MMP-9), and their tissue inhibitors (TIMP-1 and TIMP-2), could be modulated by epigenetic mechanisms, specifically, DNA methylation.

Study Methodology

  • Endometrial tissue biopsies were collected from horses in different stages of their reproductive cycle and classified into four categories based on their histological appearance, according to the Kenney and Doig scoring system.
  • The researchers evaluated the transcription levels of the genes previously mentioned, and analyzed the DNA methylation patterns of some of them (COL1A1, MMP2, MMP9, TIMP1) through a technique called pyrosequencing.

Key Findings

  • The study found that the transcript levels of both MMP2 and MMP9 genes decreased with the progression of fibrosis compared to healthy endometrium, while TIMP1 transcript levels were higher in advanced fibrosis.
  • No differences were observed in the transcript levels of COL1A1, COL1A2, COL3A1 and TIMP2.
  • MMP2 and MMP9 genes had increasing levels of methylation as endometrosis advanced, while COL1A1 showed higher methylation levels in the later stages compared to healthy endometrium. No changes were found in TIMP1 methylation levels.’

Interpretation and Implication

  • The increased methylation of MMP2 and MMP9 genes, occurring simultaneously with decrease in their transcript levels, suggests that methylation is likely repressing their transcription, thus contributing to disease progression.
  • The results indicate that the development of endometrosis is epigenetically modulated primarily through the inhibition of genes that counteract fibrosis (MMP2 and MMP9) rather than the activation of genes promoting fibrosis. This insight offers new potential therapeutic targets – perhaps by reversing the DNA methylation, the expression of these genes could be restored, impeding the progress of the disease.

Cite This Article

APA
Alpoim-Moreira J, Fernandes C, Pimenta J, Bliebernicht M, Rebordão MR, Castelo-Branco P, Szóstek-Mioduchowska A, Skarzynski DJ, Ferreira-Dias G. (2022). Metallopeptidades 2 and 9 genes epigenetically modulate equine endometrial fibrosis. Front Vet Sci, 9, 970003. https://doi.org/10.3389/fvets.2022.970003

Publication

Frontiers in veterinary science
ISSN: 2297-1769
NlmUniqueID: 101666658
Country: Switzerland
Language: English
Volume: 9
Pages: 970003

Researcher Affiliations

Alpoim-Moreira, Joana
  • CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
  • Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal.
Fernandes, Carina
  • CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
  • Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal.
Pimenta, Jorge
  • CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
  • Unidade Estratégica de Investigação e Serviços de Biotecnologia e Recursos Genéticos (UEISBR), Instituto Nacional de Investigação Agrária e Veterinária, I. P. (INIAV), Vairão, Portugal.
Bliebernicht, Miguel
  • Embriovet, Muge, Portugal.
Rebordão, Maria Rosa
  • CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
  • Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal.
  • Polytechnic of Coimbra, Coimbra Agriculture School, Coimbra, Portugal.
Castelo-Branco, Pedro
  • Faculty of Medicine and Biomedical Sciences (FMCB), University of Algarve, Faro, Portugal.
  • Algarve Biomedical Center Research Institute (ABC-RI), Faro, Portugal.
Szóstek-Mioduchowska, Anna
  • Institute of Animal Reproduction and Food Research PAS, Olsztyn, Poland.
Skarzynski, Dariusz J
  • Institute of Animal Reproduction and Food Research PAS, Olsztyn, Poland.
Ferreira-Dias, Graça
  • CIISA - Center for Interdisciplinary Research in Animal Health, Faculty of Veterinary Medicine, University of Lisbon, Lisbon, Portugal.
  • Associate Laboratory for Animal and Veterinary Sciences (AL4AnimalS), Lisbon, Portugal.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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