Epigenetic regulation of endometrium during the menstrual cycle.
ABSTRACT The endometrium undergoes morphological and functional changes during the menstrual cycle which are essential for uterine receptivity. These changes are driven by estrogen and progesterone and involve the fine control of many different genes-several of which have been identified as being epigenetically regulated. Epigenetic modification may therefore influence the functional changes in the endometrium required for successful implantation. There is, however, only limited information on epigenetic regulation in endometrium. We review the potential role of epigenetic regulation of key processes during the menstrual cycle and present our own findings following a preliminary study into global acetylation levels in the human endometrium. A changing epigenetic state is associated with the differentiation of stem cells into different lineages and thus may be involved in endometrial regeneration. Histone acetylation is implicated in the vascular endothelial growth factor pathway during angiogenesis, and studies using histone deacetylase inhibitors suggest an involvement in endometrial proliferation and differentiation. The processes of decidualization and implantation are also associated with epigenetic change and epigenetic modulators show variable expression across the menstrual cycle. Our own studies found that endometrial global histone acetylation, as determined by western blotting, changed throughout the menstrual cycle and correlated well with expected transcription activity during the different phases. This suggests that epigenetics may be involved in the regulation of endometrial gene expression during the menstrual cycle and that abnormal epigenetic modifications may therefore be associated with implantation failure and early pregnancy loss as well as with other endometrial pathologies.
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ABSTRACT: MicroRNAs (miRNAs) act as important epigenetic posttranscriptional regulators of gene expression. We aimed to gain more understanding of the complex gene expression regulation of endometrial receptivity by analyzing miRNA signatures of fertile human endometria. We set up to analyze miRNA signatures of receptive (LH + 7, n = 4) versus prereceptive (LH + 2, n = 5) endometrium from healthy fertile women. We found hsa-miR-30b and hsa-miR-30d to be significantly upregulated, and hsa-miR-494 and hsa-miR-923 to be downregulated in receptive endometrium. Three algorithms (miRanda, PicTar, and TargetScan) were used for target gene prediction. Functional analyses of the targets using Ingenuity Pathways Analysis and The Database for Annotation, Visualization and Integrated Discovery indicated roles in transcription, cell proliferation and apoptosis, and significant involvement in several relevant pathways, such as axon guidance, Wnt/β-catenin, ERK/MAPK, transforming growth factor β (TGF-β), p53 and leukocyte extravasation. Comparison of predicted miRNA target genes and our previous messenger RNA microarray data resulted in a list of 12 genes, including CAST, CFTR, FGFR2, and LIF that could serve as a panel of genes important for endometrial receptivity. In conclusion, we suggest that a subset of miRNAs and their target genes may play important roles in endometrial receptivity.Reproductive sciences (Thousand Oaks, Calif.) 08/2012; · 2.31 Impact Factor