Activated PRDM1-CREBBP Axis Contributes to Apoptosis and Impaired Invasion of Trophoblasts: A Novel Mechanism Underlying Preeclampsia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1073568 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27882527_1.fastq.gz | Fastqsanger.gz | |||
| SRR27882527_2.fastq.gz | Fastqsanger.gz | |||
| SRR27882528_1.fastq.gz | Fastqsanger.gz | |||
| SRR27882528_2.fastq.gz | Fastqsanger.gz | |||
| SRR27882529_1.fastq.gz | Fastqsanger.gz |
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Project description:To analyze the gene expression patterns in placentas collected from four PE patients and six healthy individuals.
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Project description:Preeclampsia is characterized by insufficient implantation of trophoblasts. It is relevant in the failure adaptation of trophoblasts to changes in the intrauterine embryo development environment. Fewer miRNAs have been reported on this. MiR-455-5p expressed lowly in preeclampsia but its role remains unknown. Combining cell and molecular biology methods, we suggested the function and relevant mechanisms of miR-455-5p and its potential target Shc3 in preeclampsia. In vitro, HTR-8/SVneo migrated and invaded more rapidly under H/R than in hypoxic or normoxic conditions when miR-455-5p was overexpressed. And the apoptosis of HTR-8/SVneo is in contrast to the migration and invasion in H/R. Shc3 was identified as a direct downstream target gene of miR-455-5p, where overexpression of this gene reversed the miR-455-5p impact, promoting apoptosis and suppressed invasion and migration of HTR-8/SVneo under H/R. Shc3 was highly expressed in H/R, but its level was low in isolated hypoxic or normoxic environments. Further, Shc3 overexpression is involved in placental inflammation and angiogenesis inhibition. Finally, we got the conclusion that the downregulation of miR-455-5p in preeclampsia contributes to the elevation of Shc3 in trophoblast, thereby deteriorating trophoblast cells implantation. The elevated Shc3 is associated with placental inflammation and angiogenesis inhibition. Shc3 serves as a potential biomarker for preeclampsia diagnosis and treatment.
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Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from the germinal-center (GC). However, the role of CREBBP inactivation in lymphomagenesis remains unclear. Using functional epigenomics and mouse genetics, here we define the program modulated by CREBBP in primary human GC B cells and show that CREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouse perturbs the expression of a limited set of genes involved in the regulation of signal transduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) and terminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cells exhibit proliferative advantage and show impaired plasma cell differentiation. While GC-specific loss of Crebbp was not sufficient to initiate malignant transformation, compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignancies recapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights into the mechanisms and targets by which loss of CREBBP contributes to lymphomagenesis.
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Project description:Placentation requires the proper regulation of extravillous trophoblast (EVT) migration and invasion into the decidua and maternal vasculature, processes which are initiated in physiologic hypoxic conditions. Abnormal EVT migration and/or invasion have been suggested to lead to pregnancy complications, such as preeclampsia. The objectives of this study are to determine how exposure to hypoxia impacts gene expression and cellular motility of first trimester trophoblasts, and to assess if expression of migration-associated genes is dysregulated in 2nd trimester chorionic villous samples (CVS) from preeclampsia pregnancies relative to CVS from healthy pregnancies. The 1st trimester trophoblast cell line, HTR8/SVneo, was used to investigate the relationship between hypoxia and Notch signaling in trophoblast migration and invasion. RNA sequencing and quantitative RT-PCR analyses show that exposure to hypoxia (2.5% O2) activates Notch signaling in HTR-8/SVneo. We demonstrate that exposure of HTR-8/SVneo to hypoxia induces expression of genes associated with cellular migration and invasion and increases HTR-8/SVneo cellular migration and invasion, whereas inhibition of gamma-secretase decreases Notch signaling and decreases HTR-8/SVneo migration and invasion. Analysis of RNA sequencing data from CVS of preeclampsia and uncomplicated pregnancies identified significant differentially expressed genes that are involved in cellular migration and invasion. Decreased expression of migration and invasion genes in CVS from preeclampsia pregnancies, may impair trophoblast migration and invasion in the 2nd trimester of pregnancy, resulting in the development of preeclampsia.
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Project description:Aberrantexpression of long non-coding RNAs (lncRNAs) has been reported to play a crucial role in the biological function of trophoblasts and contribute to preeclampsia (PE). Our previous study demonstrated that MIR193BHG is increased in preeclamptic placental tissues. In this study, we further explored the effects of MIR193BHG on the function of trophoblast cells and attempted to elucidate its underlying molecular mechanisms. Results showed that MIR193BHG was predominantly localized in the nucleus of HTR-8/SVneo cells. Overexpression of MIR193BHG significantly inhibited proliferation, migration and invasion of HTR-8/SVneo cells, while increasing apoptosis. Knockdown of MIR193BHG produced opposite effects.Furthermore, overexpression of MIR193BHG led to significant increases in both mRNA and protein levels of p53 compared with the control group. More importantly, knockdown of p53 rescued the negative effects induced by overexpressed MIR193BHG on cell proliferation, migration, and invasion while partially counteracting its apoptotic effects on HTR-8/SVneo cells. In conclusion, our findings suggest that MIR193BHG played a critical role in the progression of PE by regulating the expression of p53 and may serve as a novel therapeutic target for PE.
2023-10-16 | GSE245279 | GEO
Project description:Preeclampsia (PE) is a pregnancy disorder characterized by high blood pressure and proteinuria that can cause adverse health effects in both mother and fetus. There is no current cure for PE other than delivery of the fetus. While the etiology is unknown, poor placentation of the placenta due to aberrant signaling of growth and angiogenic factors has been postulated as causal factors of PE. In addition, environmental contaminants, such as the metal cadmium (Cd), have been linked to placental toxicity and increased risk of developing PE. Here, we use a translational study design to investigate genomic and epigenomic alterations in both placentas and placental trophoblasts, focused on the angiogenesis-associated transforming growth factor-beta (TGF-β) pathway. Genes within the TGF-β pathway displayed increased expression in both the preeclamptic placenta and Cd-treated trophoblasts. In addition, miRNAs that target the TGF-β pathway were also significantly altered within the preeclamptic placenta and Cd-treated trophoblasts. Integrative analysis resulted in the identification of a subset of Cd-responsive miRNAs, including miR-26a and miR-155, common to preeclamptic placentas and Cd-treated trophoblasts. These miRNAs have previously been linked to PE and are predicted to regulate members of the TGF-β pathway. Results from this study provide future targets for PE treatment.
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Project description:Early-onset preeclampsia (EOPE) is a severe hypertensive disorder of pregnancy, frequently associated with fetal growth restriction (FGR) and reduced estrogen levels due to placental dysfunction. We employed single-cell RNA sequencing (scRNA-seq) to profile placental trophoblasts from EOPE patients complicated by FGR.
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Project description:Inactivating mutations of the gene encoding for the CREBBP acetyltransferase are highly frequent in diffuse large B cell lymphoma (DLBCL, 30% of cases) and follicular lymphoma (FL, 60% of cases), the two most common cancers derived from thegerminal-center (GC). However, the role of CREBBP inactivation in lymphomagenesisremains unclear. Using functional epigenomics and mouse genetics, here we definethe program modulated by CREBBP in primary human GC B cells and show thatCREBBP regulates enhancer/super-enhancer networks, with specific roles in GC/post-GC cell fate decisions. Conditional GC-specific deletion of Crebbp in the mouseperturbs the expression of a limited set of genes involved in the regulation of signaltransduction (BCR, TLR and CD40), lineage specification (NF-κB and BCL6) andterminal B cell differentiation (PRDM1, IRF4). Consistently, Crebbp-deficient B cellsexhibit proliferative advantage and show impaired plasma cell differentiation. WhileGC-specific loss of Crebbp was not sufficient to initiate malignant transformation,compound Crebbp-haploinsufficient/BCL2-transgenic mice, mimicking the genetics ofFL and DLBCL, display an increased incidence of clonal lymphoid malignanciesrecapitulating the features of the human diseases. These findings establish CREBBPas a haploinsufficient tumor suppressor gene in GC B cells and provide insights intothe mechanisms and targes by which loss of CREBBP contributes to lymphomagenesis.
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Project description:Myelodysplastic syndrome (MDS) is considered a disease of hematopoietic stem cell (HSC) origin. To begin to unravel the molecular mechanisms underlying the deregulation of HSCs in MDS, we performed comparative gene expression profiling on Crebbp+/- and wild type HSCs. We chose to isolate HSCs from the fetal liver (FLHSC) because at this stage there were no differences in cell number between Crebbp+/- and wild type fetal livers, suggesting no overt hematopoietic differences. Thus, any change in gene expression found in Crebbp+/- FLHSCs is likely to reflect the initially compromised genetic program of HSC regulation, as opposed to that of Crebbp+/- HSCs in adult bone marrow, where secondary changes in gene expression may also occur as compensatory mechanisms for a compromised or failing hematopoietic system. We used day 14.5 post coitus FLHSC (Sca-1+,Lin-,AA4.1+,c-Kit++) from wild type (wt) and Crebbp heterozygous (ht) embryos to examine changes in gene expression before overt myelodysplastic disease manifestation. Total RNA from wt and Crebbp+/- FLHSCs was isolated, PCR-amplified using the Ovation RNA amplification system and hybridized to Affymetrix Mouse 430 2.0 expression microarrays.
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