Transcription factor C/EBPβ induces genome-wide H3K27ac and upregulates gene expression during decidualization of human endometrial stromal cells

Transcriptional regulation of the prolactin gene in the decidua differs from that in the pituitary. Several lines of evidence strongly suggest this difference is due to regulation of the prolactin gene in the decidua and other extra-pituitary tissues by tissue-specific transcription factors, which activate distinct promoters to induce prolactin gene expression in extra-pituitary sites compared with the pituitary. The human decidua is a major site of extra-pituitary expression of the prolactin gene. Here we present evidence that the transcription factor Ets-1 is critical for basal expression of the decidua-type (or decidual) prolactin promoter. Overexpression of Ets-1 significantly induces decidual prolactin promoter activity in BeWo and JAR cells that express little or no endogenous Ets-1. Conversely, a dominant/negative mutant of Ets represses basal promoter activity. Although the proximal 1.5 kb of the decidual prolactin promoter contains six Ets motifs, only the Ets motif at nt -77/-71 is essential for basal gene expression. Mutation of the Ets motif at nt -77/-71 results in an approximately 90% decrease in promoter activity, while mutation of the other Ets motifs results in only small changes. Electrophoretic mobility shift assays demonstrate that Ets proteins in decidualized endometrial stromal cells bind this Ets motif in the decidual prolactin promoter. Ets protein expression increases up to 20-fold upon induction of decidualization in endometrial stromal cells under conditions in which expression of the prolactin gene is also induced. These studies provide strong evidence for a critical role of the Ets transcription factor in basal expression of the decidual prolactin promoter.

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Faculty Opinions recommendation of Genome-wide analysis of gene expression in T cells to identify targets of the NF-kappa B transcription factor c-Rel.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1087746.540659 ◽

2007 ◽

Author(s):

E Charles Snow

Keyword(s):

Gene Expression ◽

T Cells ◽

Transcription Factor ◽

Nf Kappa B ◽

Genome Wide Analysis ◽

Genome Wide ◽

Factor C

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

Molecular Endocrinology ◽

10.1210/me.2014-1117 ◽

2014 ◽

Vol 28 (10) ◽

pp. 1656-1669 ◽

Cited By ~ 32

Author(s):

Isao Tamura ◽

Yasuyuki Ohkawa ◽

Tetsuya Sato ◽

Mikita Suyama ◽

Kosuke Jozaki ◽

...

Keyword(s):

Gene Expression ◽

Histone Modifications ◽

Stromal Cells ◽

Chromatin Immunoprecipitation ◽

Mrna Levels ◽

Promoter Regions ◽

Human Escs ◽

Endometrial Stromal Cells ◽

Genome Wide ◽

Distal Promoter

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.

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MicroRNA miR-106a-5p targets forkhead box transcription factor FOXC1 to suppress the cell proliferation, migration, and invasion of ectopic endometrial stromal cells via the PI3K/Akt/mTOR signaling pathway

Bioengineered ◽

10.1080/21655979.2021.1933679 ◽

2021 ◽

Vol 12 (1) ◽

pp. 2203-2213

Author(s):

Xinyue Zhou ◽

Zhenyu Chen ◽

Lipeng Pei ◽

Jingli Sun

Keyword(s):

Cell Proliferation ◽

Transcription Factor ◽

Signaling Pathway ◽

Stromal Cells ◽

Mtor Signaling ◽

Migration And Invasion ◽

Mtor Signaling Pathway ◽

Endometrial Stromal Cells ◽

Forkhead Box

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The AML-associated K313 mutation enhances C/EBPα activity by leading to C/EBPα overexpression

Cell Death and Disease ◽

10.1038/s41419-021-03948-6 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ian Edward Gentle ◽

Isabel Moelter ◽

Mohamed Tarek Badr ◽

Konstanze Döhner ◽

Michael Lübbert ◽

...

Keyword(s):

Gene Expression ◽

Cell Culture ◽

Transcription Factor ◽

Transcription Factors ◽

Transcriptional Activity ◽

Target Gene ◽

Wild Type ◽

Elevated Expression ◽

Factor C ◽

Acute Myeloid

AbstractMutations in the transcription factor C/EBPα are found in ~10% of all acute myeloid leukaemia (AML) cases but the contribution of these mutations to leukemogenesis is incompletely understood. We here use a mouse model of granulocyte progenitors expressing conditionally active HoxB8 to assess the cell biological and molecular activity of C/EBPα-mutations associated with human AML. Both N-terminal truncation and C-terminal AML-associated mutations of C/EBPα substantially altered differentiation of progenitors into mature neutrophils in cell culture. Closer analysis of the C/EBPα-K313-duplication showed expansion and prolonged survival of mutant C/EBPα-expressing granulocytes following adoptive transfer into mice. C/EBPα-protein containing the K313-mutation further showed strongly enhanced transcriptional activity compared with the wild-type protein at certain promoters. Analysis of differentially regulated genes in cells overexpressing C/EBPα-K313 indicates a strong correlation with genes regulated by C/EBPα. Analysis of transcription factor enrichment in the differentially regulated genes indicated a strong reliance of SPI1/PU.1, suggesting that despite reduced DNA binding, C/EBPα-K313 is active in regulating target gene expression and acts largely through a network of other transcription factors. Strikingly, the K313 mutation caused strongly elevated expression of C/EBPα-protein, which could also be seen in primary K313 mutated AML blasts, explaining the enhanced C/EBPα activity in K313-expressing cells.

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Repressor- and Activator-Type Ethylene Response Factors Functioning in Jasmonate Signaling and Disease Resistance Identified via a Genome-Wide Screen of Arabidopsis Transcription Factor Gene Expression

PLANT PHYSIOLOGY ◽

10.1104/pp.105.068544 ◽

2005 ◽

Vol 139 (2) ◽

pp. 949-959 ◽

Cited By ~ 348

Author(s):

Ken C. McGrath ◽

Bruno Dombrecht ◽

John M. Manners ◽

Peer M. Schenk ◽

Cameron I. Edgar ◽

...

Keyword(s):

Gene Expression ◽

Transcription Factor ◽

Disease Resistance ◽

Transcription Factor Gene ◽

Response Factors ◽

Factor Gene ◽

Ethylene Response ◽

Genome Wide ◽

A Genome ◽

Ethylene Response Factors

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Shp2 in uterine stromal cells critically regulates on time embryo implantation and stromal decidualization by multiple pathways during early pregnancy

PLoS Genetics ◽

10.1371/journal.pgen.1010018 ◽

2022 ◽

Vol 18 (1) ◽

pp. e1010018

Author(s):

Jianghong Cheng ◽

Jia Liang ◽

Yingzhe Li ◽

Xia Gao ◽

Mengjun Ji ◽

...

Keyword(s):

Gene Expression ◽

Signaling Pathways ◽

Stromal Cells ◽

Embryo Implantation ◽

Endometrial Stromal Cells ◽

Conditional Deletion ◽

Enhancer Binding Protein ◽

Epithelial Remodeling ◽

Multiple Signaling ◽

Transcription 3

Approximately 75% of failed pregnancies are considered to be due to embryo implantation failure or defects. Nevertheless, the explicit signaling mechanisms governing this process have not yet been elucidated. Here, we found that conditional deletion of the Shp2 gene in mouse uterine stromal cells deferred embryo implantation and inhibited the decidualization of stromal cells, which led to embryonic developmental delay and to the death of numerous embryos mid-gestation, ultimately reducing female fertility. The absence of Shp2 in stromal cells increased the proliferation of endometrial epithelial cells, thereby disturbing endometrial epithelial remodeling. However, Shp2 deletion impaired the proliferation and polyploidization of stromal cells, which are distinct characteristics of decidualization. In human endometrial stromal cells (hESCs), Shp2 expression gradually increased during the decidualization process. Knockout of Shp2 blocked the decidual differentiation of hESCs, while Shp2 overexpression had the opposite effect. Shp2 knockout inhibited the proliferation of hESCs during decidualization. Whole gene expression profiling analysis of hESCs during the decidualization process showed that Shp2 deficiency disrupted many signaling transduction pathways and gene expression. Analyses of hESCs and mouse uterine tissues confirmed that the signaling pathways extracellular regulated protein kinases (ERK), protein kinase B (AKT), signal transducer and activator of transcription 3 (STAT3) and their downstream transcription factors CCAAT/enhancer binding protein β (C/EBPβ) and Forkhead box transcription factor O1 (FOXO-1) were involved in the Shp2 regulation of decidualization. In summary, these results demonstrate that Shp2 plays a crucial role in stromal decidualization by mediating and coordinating multiple signaling pathways in uterine stromal cells. Our discovery possibly provides a novel key regulator of embryo implantation and novel therapeutic target for pregnancy failure.

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