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The histone demethylase KDM5C represses trophoblast proliferation and invasion in woman with recurrent miscarriage [ChIP-seq]

ABSTRACT: KDM5C is a H3K4- specific demethylase, which has multiple biological roles in development and disease. However, the role of KDM5C in trophoblasts at the maternal-fetal interface remains unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from patient with recurrent miscarriage (RM). Trophoblasts proliferation and invasion was inhibited by KDM5C overexpression and was enhanced by KDM5C knockdown. Interestingly, KDM5C knockdown promoted trophoblast invasion in villous explant culture system. RNA-seq and ChIP-seq analyses revealed that KDM5C exerts anti-proliferation and anti-invasion effect by directly modulating H3K4 methylation level to repress the expression of a number of key regulatory genes. We show that two of these genes, TGFβ2, RAGE, are essential for the proliferation and invasion of trophoblasts. Taken together, our results show that the KDM5C is regulator of trophoblast function during early pregnancy and indicated that KDM5C may be involved in the pathogenesis of RM. To characterize genome-wide H3K4me3 chromatin-state of HTR-8/SVneo cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE141717 | GEO | 2022/12/16

REPOSITORIES: GEO

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The histone demethylase KDM5C represses trophoblast proliferation and invasion in woman with recurrent miscarriage [RNA-seq]

Project description:KDM5C is a H3K4- specific demethylase, which has multiple biological roles in development and disease. However, the role of KDM5C in trophoblasts at the maternal-fetal interface remains unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from patient with recurrent miscarriage (RM). Trophoblasts proliferation and invasion was inhibited by KDM5C overexpression and was enhanced by KDM5C knockdown. Interestingly, KDM5C knockdown promoted trophoblast invasion in villous explant culture system. RNA-seq and ChIP-seq analyses revealed that KDM5C exerts anti-proliferation and anti-invasion effect by directly modulating H3K4 methylation level to repress the expression of a number of key regulatory genes. We show that two of these genes, TGFβ2, RAGE, are essential for the proliferation and invasion of trophoblasts. Taken together, our results show that the KDM5C is regulator of trophoblast function during early pregnancy and indicated that KDM5C may be involved in the pathogenesis of RM. Next Generation Sequencing Facilitates Quantitative Analysis of HTR-8/SVneo cells transduced with control or KDM5C-expression vector, and HTR-8/SVneo cells transduced with NC or KDM5C shRNA-expression vector,

2022-12-16 | GSE141716 | GEO

The histone demethylase KDM5C represses trophoblast proliferation and invasion in woman with recurrent miscarriage

Project description:KDM5C is a histone H3K4-specific demethylase, which has been shown to play a key role in biological disease and development. However, the role of KDM5C in trophoblasts at early pregnancy is currently unknown. Here, we showed that KDM5C was upregulated in placental trophoblasts from recurrent miscarriage (RM) patients compared with healthy controls (HCs). Trophoblast proliferation and invasion was inhibited by KDM5C overexpression and was promoted by KDM5C knockdown. Transcriptome sequencing revealed that elevated KDM5C exerted anti-proliferation and anti-invasion effects by repressing the expression of essential regulatory genes. The combination analysis of RNA-seq, ChIP-seq and CUT&Tag assay showed that KDM5C overexpression leads to the reduction of H3K4me3 on the promoters and the corresponding downregulation of expression of several regulatory genes in trophoblasts. Among these genes, TGFβ2 and RAGE are essential for the proliferation and invasion of trophoblasts. Importantly, overexpression of KDM5C by a systemically delivered KDM5C adenovirus vector (Ad-KDM5C) promoted embryo resorption rate in mouse. Our results support that KDM5C is an important regulator of the trophoblast function during early pregnancy, and suggesting that KDM5C activity could be responsible for epigenetic alterations seen RM disease. This SuperSeries is composed of the SubSeries listed below.

2022-12-16 | GSE141718 | GEO

The YY1/MMP2 axis promotes trophoblast invasion at the maternal-fetal interface

Project description:YY1 is a sequence-specific DNA-binding transcription factor that has many important biological roles. However, its function in trophoblasts at the maternal-foetal interface remains to be elucidated. In this study, we used an mRNA microarray and quantitative reverse transcription-PCR and compared the YY1 mRNA expression level in trophoblasts between patients with recurrent miscarriage (RM) and healthy control subjects. Our results revealed that YY1 mRNA expression was significantly lower in the trophoblasts of the RM group compared with the healthy control group. Furthermore, immunofluorescence and immunohistochemical data showed that YY1 was highly expressed in human placental villi during early pregnancy, especially in cytotrophoblast cells and invasive extravillous trophoblasts, and it was expressed at a much lower level in the placental villi of term pregnancy. YY1 overexpression enhanced the invasion and proliferation of trophoblasts, while knockdown of YY1 repressed these effects. Antibody array screening revealed that YY1 significantly promoted MMP2 expression in trophoblasts. Bioinformatics analysis identified three YY1-binding sites in the MMP2 promoter region, and chromatin immunoprecipitation analysis verified that YY1 binds directly to its promoter region. Importantly, inhibition of YY1 by siRNA clearly decreased trophoblast invasion in an ex vivo explant culture model. Overall, our findings revealed a new regulatory pathway of YY1/MMP2 in trophoblast cells invasion during early pregnancy, and indicated that YY1 may be involved in the pathogenesis of RM. Total RNA was isolated using Trizol from trophoblast cells from three healthy controls (HC) and three recurrent miscarriage (RM) patients. Total RNA were extracted and used for hybridizing Affymetrix chips (GeneChipÂ® Human Transcriptome Array 2.0(HTA2.0)). Data were normalised by gcRMA method and raw p-values adjusted by Bonferroni procedure (1%).

2016-01-21 | E-GEOD-76862 | biostudies-arrayexpress

The YY1/MMP2 axis promotes trophoblast invasion at the maternal-fetal interface

2016-01-21 | GSE76862 | GEO

The histone demethylase KDM5C represses trophoblast proliferation and invasion in woman with recurrent miscarriage [CUT & Tag]

Project description:To characterize genome-wide KDM5C traget genes in HTR-8/SVneo cells transduced with KDM5C-expression vector by CUT&Tag.

2022-12-16 | GSE200540 | GEO

Integrated microRNA and secretome analysis of human endometrial organoid reveal the miR-3194-5p/Aquaporin/S100A9 module in regulating trophoblast functions

Project description:Successful placentation requires delicate communication between endometrium and trophoblasts. The invasion and integration of trophoblasts into the endometrium during early pregnancy is crucial to placentation. Dysregulation of these functions is associated with various pregnancy complications such as miscarriage and preeclampsia. The endometrial microenvironment exerts an important influence on trophoblast cell functions. We hypothesized that the hormonal environment regulates the miRNA profile and secretome of the human endometrial gland, which subsequently modulates trophoblast functions during early pregnancy. By establishing the first secretome profiles and miRNA atlas of these endometrial organoids to the hormonal changes followed by trophoblast functional assays, we demonstrated that sex steroid hormones modulate aquaporins (AQP)1/9 and S100A9 secretions through miR-3194 activation in endometrial epithelial cells, which in turn enhanced trophoblast migration and invasion during early pregnancy.

2023-05-10 | PXD036535 | Pride

Low chorionic villous succinate accumulation associates with recurrent spontaneous abortion risk

Project description:Dysregulated extravillous trophoblast invasion and proliferation are known to increase the risk of recurrent spontaneous abortion (RSA); however, the underlying mechanism remains unclear. Herein, in our retrospective observational case-control study we show that villous samples from RSA patients, compared to healthy controls, display reduced succinate dehydrogenase complex iron sulfur subunit (SDHB) DNA methylation, elevated SDHB expression, and reduced succinate levels, indicating that low succinate levels correlate with RSA. Moreover, we find high succinate levels in early pregnant women are correlated with successful embryo implantation. SDHB promoter methylation recruited MBD1 and excluded c-Fos, inactivating SDHB expression and causing intracellular succinate accumulation which mimicked hypoxia in extravillous trophoblasts cell lines JEG3 and HTR8 via the PHD2-VHL-HIF-1α pathway; however, low succinate levels reversed this effect and increased the risk of abortion in mouse model. This study reveals that abnormal metabolite levels inhibit extravillous trophoblast function and highlights an approach for RSA intervention.

2021-10-06 | MTBLS2148 | MetaboLights

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (ChIP-Seq I)

Project description:Primed enhancers are marked by histone H3K4 mono-methylation (H3K4me1), and the conversion to active enhancers involves acetylation of histone H3K27 (H3K27Ac). However, whether active enhancers are regulated remains unclear. Here we report a biochemical complex consisting of a potential chromatin reader (RACK7) and a histone demethylase (KDM5C) that occupies many active enhancers in a breast cancer cell line. Loss of RACK7 or KDM5C results in hyperactive enhancers marked by H3K4me3 and H3K27Ac, and characterized by an increased eRNA transcription and elevated expression of nearby genes. Loss of RACK7 or KDM5C also leads to increased cell invasion and migration, and enhanced tumor growth. We propose that RACK7/KDM5C functions as an enhancer âbrakeâ to ensure appropriate enhancer activities in the cell. Our findings provide important insight into histone H3K4 methylation dynamics at enhancers and reveal a molecular mechanism that controls the activities of active enhancers, which when compromised, can contribute to tumorigenesis. ChIP-seq data of RACK7, KDM5C and histone modifications in parental and RACK7-KO ZR-75-30 cells.

2016-04-07 | E-GEOD-71323 | biostudies-arrayexpress

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (ChIP-Seq II)

2016-04-07 | E-GEOD-76637 | biostudies-arrayexpress

A Surveillance System of Active Enhancers by a RACK7-histone Demethylase Complex (RNA-Seq I)

2016-04-07 | E-GEOD-71325 | biostudies-arrayexpress