Unknown,Transcriptomics,Genomics,Proteomics

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Gene expression profiling of C/EBPM-NM-2- and STAT3-deficient human endometrial stromal cells (HESC)

ABSTRACT: Our previous studies have shown that C/EBPM-NM-2 plays a critical role in human endometrial stromal decidualization. In order to identify the molecular pathways regulated by C/EBPM-NM-2 during decidualization, we performed gene expression profiling using RNA isolated from normal and C/EBPM-NM-2-deficient human endometrial stromal cells. The microarray results revealed that several key regulators of stromal differentiation, such as BMP2, Wnt4, IL-11RM-NM-1 and STAT3, operate downstream of C/EBPM-NM-2 during decidualization. Further studies revealed that STAT3 is a direct target of C/EBPM-NM-2 and plays an important role in cytokine signal during the decidualization process. Gene expression profiling, using STAT3-deficient HESCs, showed an extensive overlap of pathways downstream of STAT3 and C/EBPM-NM-2 during stromal cell differentiation. We employed a siRNA strategy to suppress C/EBPM-NM-2 or STAT3 mRNA expression in HESCs and then performed microarray analysis to identify its downstream target genes. Further, using a similar strategy, we focused on STAT3, a C/EBPM-NM-2 target gene, and identified the commone pathways downstream of both C/EBPM-NM-2 and STAT3.

ORGANISM(S): Homo sapiens

SUBMITTER: Wei Wang

PROVIDER: E-GEOD-41473 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Embryo implantation into a receptive endometrium is tightly regulated by a variety of maternal factors, including cytokines, growth factors and transcription factors. Previous studies identified the leukaemia inhibitory factor (LIF), produced in uterine glands, as an essential factor for implantation. It was shown that LIF acts via its cell surface receptor to activate the transcription factor STAT3 in the uterine epithelial cells. However, the mechanisms via which STAT3 promotes uterine receptivity remain unknown. To address the molecular pathways regulated by STAT3 in the uterus, we created mice in which Stat3 gene is conditionally inactivated in uterine epithelium. These mutant mice are infertile due to implantation failure and exhibit a lack of embryo attachment to the luminal epithelium. Gene expression profiling of the epithelial tissue impaired in STAT3 activation revealed dysregulated expression of specific components of junctional complexes, including E-cadherin, M-NM-2-catenin, and claudins, which critically regulate epithelial cell polarity and embryo attachment. Additionally, mice lacking functional epithelial STAT3 showed markedly reduced stromal proliferation and differentiation, indicating that this transcription factor controls stromal function via a paracrine mechanism. The stromal defect arose from a drastic reduction in the production of several members of the epidermal growth factor (EGF) family in luminal epithelium of mutant uteri and consequent lack of activation of EGF receptor signaling and mitotic activity in the stromal cells. Collectively, our results uncovered intricate signaling networks operating downstream of STAT3 in uterine epithelium that regulate epithelial cell polarity, and stromal proliferation and differentiation, which are critical determinants of successful implantation. To identify the downstream targets of STAT3 in mouse uterine epithelial cells during pregnancy, we performed gene expression profling of mouse uterine epithelial cells on day 4 of pregnancy between Stat3 flox control and SW d/d mice. This led to the identification of several junctional molecules (Claudins and Catenins) that are negatively regulated by STAT3 at the time of implantation. Mouse uteirne epithelial cells were isolated from control and knockout mice on the morning of day 4 of pregnancy. (n=3 for each sample), pooled total RNA from these cells was then hybridized to high density affymetrix microarrays according to the Affymetrix protocol (Mouse Genome 430A 2.0 Array) .

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Gene expression profiling of C/EBPM-NM-2- and STAT3-deficient human endometrial stromal cells (HESC)

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