Updates in the Field of Endometriosis: Epigenetics

Research has shown that epigenetic alterations can cause or worsen endometriosis.

Key Points

Highlights:

• Grimstad and Decherney discuss the epigenetic influences that drive endometriosis disease progression.

Importance:

• Research has yet to elucidate the genetic and molecular mechanisms that cause endometriosis. Understanding the pathogenesis of these disease will allow researcher to develop a cure and will lead to better treatment at the hands of a healthcare professional.

What’s done here?

• The authors gathered and consolidated information pertaining to the relationship between endometriosis and epigenetics. They interspersed this knowledge with relevant research.

Key points:

• Epigenetic alterations refer to stable changes in gene expression that are heritable, but these changes do not affect the underlying DNA sequence. These changes that occur over the course of a lifetime are conserved through cycles of cell replication. DNA methylation, histone methylation, acetylation, sumoylation, ubiquitylation, phosphorylation, chromatin remodeling, and RNA transcriptional changes are all examples of epigenetic changes.
• DNA Methylation:
  • The following DNA Methyltransferases (DNMTs) used for DNA methylation are over expressed in individuals with endometriosis: DNMT1, DNMT3A, and DNMT3B. DNTMs in individuals without endometriosis have a varying pattern of expression, whereas DNMTs in individuals with endometriosis remains at a high level of expression.
  • Endometriosis appears to have a more directed pattern of hypermethylation. Endometrial stromal cells have a concentrated area of hypermethylation at the ends of chromosomes. Additionally, it is believed that some areas of hypermethylation can be conserved.
• Histone Modifications
  • Endometriotic stromal cells tend to be hypoacetylated.
  • Some studies have shown that histone deacetylases (HDAC), namely HDAC1 and HDAC2, are expressed differently in individuals with endometriosis; however, the results of these studies must be further verified. Increased HDAC activity leads to hypoacetylation of the promoter regions, which then results in increased cell proliferation. This process can be inhibited using HDAC inhibitors that acetylate H3 and H4.
• Chromatin Architecture Changes
  • Alters in chromatin architecture changes the expression and activity of estrogen receptors (ER).
  • Endometriotic cysts and endometrioid carcinoma is said to stem from somatic mutations of chromatin modelers.
• MicroRNA (miRNA)
  • Previous studies have revealed that over 50 different miRNAs are expressed differently in individuals with endometriosis.
  • Differently expressed miRNAs found in women with endometriosis can impact gene regulation, protein expression, control of inflammatory pathways, embryo quality, embryo implantation, and apoptosis.
  • Various studies seek to identify miRNAs that can act as biomarkers for the illness.
• Nuclear Receptor (NR) Modulation
  • NR receptors can cause endometriotic lesions by altering the signaling pathways that are mediated by estrogen.
  • Coregulators and inflammatory molecules can activate NRs.
  • Research has shown that there are 16 NRs downregulated and 19 NRs upregulated in endometriotic tissue.
• Hormone Modulation
  • Endometriosis cells are thought to survive due to their proestrogenic state and their resistance to progesterone.
  • It is believed that alterations in hormone receptors can led to endometriosis.
  • The authors maintain that hormonal changes lead to many alterations downstream.
• ER Modulation
  • Varying ERα to ERβ ratios are indicative of varying estrogen receptivity. The results from previous studies provide conflicting results regarding the ratio of ERα to ERβ and the link to endometriosis. Most studies state that individuals with endometriosis have higher ERα to ERβ ratios. There are many theories, such as hypomethylation and downregulation, which explain the change in the aforementioned ratio. The authors state that looking at tissue location and disease progression can bridge the gap between the previously stated hypotheses.
• Progesterone Receptor Resistance
  • Cell growth in endometriosis has been attributed to the resistance and downregulation of PR-B.
  • Coactivators, such as Hic-5, that regulate PR are differentially expressed in endometriosis. The authors state that drugs that target coregulators could potentially be efficient therapies.
  • Research has yet to determine the exact expression patterns for PR-B in tissues related to endometriosis.
• Aromatase
  • Estrogen and the gene, CYP19 on chromosome 15q21, which codes for Aromatase, an enzyme, is upregulated in women with endometriosis. It is thought that this upregulation is linked to promoter region of this gene; however, further research is needed to understand the exact mechanism.
• Steroid Factor-1 (SF-1)
  • Protein and mRNA levels of SF-1 are higher in endometriotic cells; however, SF-1 is typically absent in endometriosis cells. This irregular expression of SF-1 could potentially be attributed to improper methylation and acetylation.
  • An increase in SF-1 leads to aromatase and steroidogenic acute regulatory protein activation, which ultimately results in increased estrogen production.
• COX 2
  • Hypomethylation and ERβ activations results in the upregulation of COX-2.
  • COX-2 is thought to be involved in dysmenorrhea and inflammation.
• HOXA10
  • Hypermethylation and hypoacetylation within the promoter of HOXA10 gene is thought to result in endometriosis or further the progression of the illness.
  • Similar to HOX10, FOX01 is also down regulated in endometriosis.
• IGFPB-1
  • FOX01 and HOXA10 expression may causes downregulation of IGFPB-1; however, research has yet to determine whether ICFPB-1 is significant for the pathogenesis of endometriosis.
• C/EBPα
  • It is thought that these transcription factors are downregulated in endometriosis; however inhibiting the HDACs that regulate C/EBPα can result in decreased cell proliferation and increased apoptosis.
• E-Cadherin
  • This cell junction is downregulated in endometriosis possibly due to hypermethylation.
• Research has turned to growth factors, signal transduction related genes, cell adhesion, cell motility, and expression of MMPs in order to determine the epigenetic basis of endometriosis.
• In the future, epigenetics can help with diagnosis and treatment of endometriosis.

This summary is a part of the future of endometriosis research, whic summarises the progress made in this field. The developments have been delineated in a 2017 issue of Clinical Obstetrics and Gynecology. For updates specific to a given topic namely surgery, genetics, imaging, fertility and fertility preservation, one can consult the issue above of Clinical Obstetrics and Gynecology or please look at the summaries for each topic, found in Endonews.

Lay Summary

In this chapter titled “A Review of the Epigenetic Contributions to Endometriosis,” Grimstad and Decherney examine various epigenetic influences that drive endometriosis disease progression. The epigenetic alterations they discuss include DNA methylation, histone modification, chromatin architecture changes, nuclear receptor modulation, hormone modulation, and progesterone receptor resistance, as well as changes in the expression levels of miRNA, aromatase, steroid factor-1, COX-2, HOXA10, FOX01, IGFPB-1, C/EBPα, and E-Cadherins. They also briefly discussed other less prominent epigenetic studies. The authors claim that epigenetics can be used in the field of endometriosis for diagnosis and treatment. Over the course of the paper, the reader is made aware of the lack of data available in this sub-field of endometriosis research. The authors also use the last paragraph to discuss limitations faced by researchers who seek to understand endometriosis at an epigenetic level.

It is important to note that the full chapter on epigenetics and endometriosis can be found in a 2017 issue of Clinical Obstetrics and Gynecology. For updates specific to another given topic namely surgery, genetics, imaging, fertility and fertility preservation, one can consult the aforementioned issue of Clinical Obstetrics and Gynecology or look at the summaries found on Endonews. Endonews also provides an all-encompassing summary.

Research Source: https://www.ncbi.nlm.nih.gov/pubmed/28742579