Genome-Wide Analysis of Histone Modifications in Human Endometrial Stromal Cells

Abstract

Dramatic changes of gene expressions occur in human endometrial stromal cells (ESCs) during decidualization. The changes in gene expression are associated with changes of chromatin structure, which are regulated by histone modifications. Here we investigated genome-wide changes in histone modifications associated with decidualization in human ESCs using chromatin immunoprecipitation combined with next-generation sequencing. ESCs were incubated with estradiol and medroxyprogesterone acetate for 14 days to induce decidualization. The chromatin immunoprecipitation-sequence data showed that induction of decidualization increased H3K27ac and H3K4me3 signals in many genomic regions but decreased in only a few regions. Most of the H3K27ac-increased regions (80%) and half of the H3K4me3-increased regions were located in the distal promoter regions (more than 3 kb upstream or downstream of the transcription start site). RNA sequence showed that induction of decidualization up-regulated 881 genes, 223 of which had H3K27ac- or H3K4me3-increased regions in the proximal and distal promoter regions. Induction of decidualization increased the mRNA levels of these genes more than it increased the mRNA levels of genes without H3K27ac- or H3K4me3-increased regions. Pathway analysis revealed that up-regulated genes with the H3K27ac- or H3K4me3-increased regions were associated with the insulin signaling, which may be involved in glucose uptake that is necessary for ESCs to undergo decidualization. These results show that histone modification statuses on a genome-wide basis change in human ESCs during decidualization. The main changes of histone modifications are increases of H3K27ac and H3K4me3 in both the proximal and distal promoter regions, which are involved in the up-regulation of gene expression that occurs during decidualization.

The distal upstream region of insulin-like growth factor–binding protein-1 enhances its expression in endometrial stromal cells during decidualization

“…We also found that the increase of H3K27ac in the distal regions as well as in the proximal regions was associated with the up-regulation of gene expression during decidualization (8). These facts led us to speculate that the H3K27ac-increased regions in the distal regions play key roles as enhancer regions in the regulation of gene expressions during decidualization.…”

“…Genome-wide analyses revealed a number of genes that are up-regulated or down-regulated by decidualization in human ESCs (5)(6)(7)(8). Gene expression including transcription involves a change of chromatin structure, which can be regulated by epigenetic mechanisms such as histone modifications (9,10).…”

“…By using a genome-wide ChIP-sequence approach, we identified a number of genes in which the H3K27ac level was increased during decidualization in human ESCs (8).…”

Hmgn1 acts downstream of C/EBPβ to regulate the decidualization of uterine stromal cells in mice

“…2,3 Proper decidualization is essential for continued embryonic development within the uterus and achieving successful pregnancy, because impaired decidualization can lead to miscarriage or even pathological pregnancy such as preeclampsia or intrauterine growth restriction. 2,4 Genome-wide microarray analyses have identified a number of genes that are up-regulated or down-regulated during decidualization, suggesting the presence of complex mechanisms of gene expression. 4 To date, accumulating data have shown that gene expression involves a change of chromatin structure which can be regulated by structural proteins such as the high mobility group nucleosomal binding (Hmgn) family.…”

“…2,4 Genome-wide microarray analyses have identified a number of genes that are up-regulated or down-regulated during decidualization, suggesting the presence of complex mechanisms of gene expression. 4 To date, accumulating data have shown that gene expression involves a change of chromatin structure which can be regulated by structural proteins such as the high mobility group nucleosomal binding (Hmgn) family. 5,6 Hmgn proteins are architectural nonhistone chromosomal proteins that bind specifically to nucleosome core particle, reduce the compaction of the chromatin fiber, alter the structure of chromatin and thereby affect a variety of DNA-dependent activities such as transcription, replication, recombination and DNA repair.…”