Endometriosis Is Characterized by a Distinct Pattern of Histone 3 and Histone 4 Lysine Modifications

Abstract

Background: The histone modification patterns in endometriosis have not been fully characterized. This gap in knowledge results in a poor understanding of the epigenetic mechanisms (and potential therapeutic targets) at play. We aimed to (1) assess global acetylation status of histone 3 (H3) and histone 4 (H4), (2) measure levels of H3 and H4 lysine (K) acetylation and methylation, and (3) to identify histone acetylation patterns in promoter regions of candidate genes in tissues from patients and controls. Methods: Global and K-specific acetylation/methylation levels of histones were measured in 24 lesions, 15 endometrium from patients, and 26 endometrium from controls. Chromatin immunoprecipitation (ChIP)-polymerase chain reaction was used to determine the histone acetylation status of the promoter regions of candidate genes in tissues. Results: The lesions were globally hypoacetylated at H3 (but not H4) compared to eutopic endometrium from controls. Lesions had significantly lower levels of H3K9ac and H4K16ac compared to eutopic endometrium from patients and controls. Tissues from patients were hypermethylated at H3K4, H3K9, and H3K27 compared to endometrium from controls. The ChIP analysis showed hypoacetylation of H3/H4 within promoter regions of candidate genes known to be downregulated in endometriosis (e.g., HOXA10, ESR1, CDH1, and p21 WAF1/Cip1 ) in lesions versus control endometrium. The stereoidogenic factor 1 (SF1) promoter region was enriched for acetylated H3 and H4 in lesions versus control tissues, correlating with its reported high expression in lesions. Conclusions: This study describes the histone code of lesions and endometrium from patients with endometriosis and provides support for a possible role of histone modification in modulation of gene expression in endometriosis.

Enhancer of Zeste homolog 2 (EZH2) induces epithelial-mesenchymal transition in endometriosis

“…Our findings, along with increased H3K9me3, are in broad agreement with their results that higher methylation levels of H3K9 were detected in ectopic endometrium 38 .…”

“…In addition, our findings are in broad agreement with high levels of H3K9me3, H3K27me3 and EZH2 in endometriotic cells 37 and with increased H3K9 and H3K27 methylation in endometriosis 38 .…”

H3K27me3 is an Epigenetic Mark of Relevance in Endometriosis

“…Previous studies in our laboratory showed that methylation levels of H3K27 were significantly higher in endometriotic lesions and endometrium from patients compared to endometrium of controls, using an immunoassay that does not distinguish among mono-, di-, and trimethylation. 17 The molecular roles of H3K27me1, H3K27me2, and H3K27me3 are known to be different; therefore, it is important to elucidate their respective levels in endometriosis tissues and also to take into account cellular compartment (stroma vs glands). In order to do so and to validate the results obtained with the immunoassay analysis, we analyzed the levels of H3K27me3 in human endometriotic and endometrial tissues on a TMA by IHC.…”

“…14,15 We have previously shown that endometriotic lesions are characterized by hypoacetylation of H3K9 and H3K16 and hypermethylation of H3K4, H3K9, and H3K27. 16,17 Based on these findings, we aimed to further study the relevance of H3K27me3 specifically in endometriosis.…”

Epigenetic: A new approach to etiology of infertility

“…Histone acetylation is generally associated with the activation of a gene expression. The analysis of the chromatin immunoprecipitation (ChIP) conducted by Monteiro et al 48 showed the hypoacetylation on the H3/H4 at the promoter regions of candidate genes was down regulated in endometriosis, namely HOXA10, ESR1, CDH1 and p21. 48 On the other hand, the steroidogenic factor 1 promoter gene underwent increased acetylation of H3 and H4 which correlated with the high expression of the gene.…”