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Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion.

ABSTRACT: Invasion of the trophoblast into the maternal decidua is regulated by both the trophoectoderm and the endometrial stroma, and entails the action of tissue remodeling enzymes. Trophoblast invasion requires the action of metalloproteinases (MMPs) to degrade extracellular matrix (ECM) proteins and in turn, decidual cells express tissue inhibitors of MMPs (TIMPs). The balance between these promoting and restraining factors is a key event for the successful outcome of pregnancy. Gene expression is post-transcriptionally regulated by histone deacetylases (HDACs) that unpacks condensed chromatin activating gene expression. In this study we analyze the effect of histone acetylation on the expression of tissue remodeling enzymes and activity of human endometrial stromal cells (hESCs) related to trophoblast invasion control. Treatment of hESCs with the HDAC inhibitor trichostatin A (TSA) increased the expression of TIMP-1 and TIMP-3 while decreased MMP-2, MMP-9 and uPA and have an inhibitory effect on trophoblast invasion. Moreover, histone acetylation is detected at the promoters of TIMP-1 and TIMP-3 genes in TSA-treated. In addition, in an in vitro decidualized hESCs model, the increase of TIMP-1 and TIMP-3 expression is associated with histone acetylation at the promoters of these genes. Our results demonstrate that histone acetylation disrupt the balance of ECM modulators provoking a restrain of trophoblast invasion. These findings are important as an epigenetic mechanism that can be used to control trophoblast invasion.

SUBMITTER: Estella C

PROVIDER: S-EPMC3266920 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeDuring early embryo invasion (48 h after embryo attachment), what functional changes accompany dynamic gene expression alterations in human endometrial stromal cells?MethodIn the present study, primary human endometrial stromal cells (phESCs) were cultured. After in vitro decidualization, primary human endometrial stromal cells (phESCs) were cultured with blastocysts for 48 h. During this process, blastocysts attached and invaded the phESCs (embryo-invaded primary human endometrial stromal cells, ehESCs). We performed comprehensive transcriptomic profiling of phESCs (two replicates) and ehESCs (five replicates) and analyzed the differentially expressed gene (DEGs) sets for gene ontology (GO) terms and Kyoto encyclopaedia of genes and genomes (KEGG) pathway enrichment. To analyse potential connectivity patterns between the transcripts in these DEG sets, a protein-protein interaction (PPI) network was constructed using the STRING database.ResultsA total of 592 DEGs were identified between phESCs and ehESCs after embryo invasion. Primary human endometrial stromal cells underwent significant transcriptomic changes that occur in a stepwise fashion. Oxidative phosphorylation, mitochondrial organization, and P53 signalling pathways were significantly altered in phESCs after embryo invasion. EP300 may play a key role in regulating transcription via chromatin remodelling to facilitate the adaptive gene expression changes that occur during embryo invasion.ConclusionsOur data identify dynamic transcriptome changes that occur in endometrial stromal cells within 48 h after embryo invasion. The pathways that we found to be enriched in phESCs after embryo invasion (oxidative phosphorylation, mitochondrial organization, and P53 signalling) may represent novel mechanisms underlying embryo implantation, and may illuminate the reasons that some women experience reproductive failure.Key messagesHuman endometrial stromal cells have undergone changes in gene expression regulation and signalling pathways during the embryo invasion.Mitochondrial-oxidative phosphorylation changes in human stromal cells manifested as down-regulation of gene expression in the electron transport chain.TP53 signalling pathway and transcriptional regulator EP300 assist stromal cells to get adaptive changes during embryo invasion phase.

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Inhibition of histone deacetylase activity in human endometrial stromal cells promotes extracellular matrix remodelling and limits embryo invasion.

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