The elevated YTHDC1 affects trophoblastic function and induces preterm birth in ART conception via augmenting RPL37 translation
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ABSTRACT:
PROVIDER: PRJNA1022799 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR26242979_1.fastq.gz | Fastqsanger.gz | |||
| SRR26242979_2.fastq.gz | Fastqsanger.gz | |||
| SRR26242980_1.fastq.gz | Fastqsanger.gz | |||
| SRR26242980_2.fastq.gz | Fastqsanger.gz | |||
| SRR26242981_1.fastq.gz | Fastqsanger.gz |
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Project description:Here, it is shown that YTHDC1 was significantly increased in the human preterm placenta after ART and the murine preterm placenta after E2 exposure. Overexpression of YTHDC1 significantly promoted the proliferation, migration, and invasion of trophoblast cells, but inhibited their apoptosis. Knockdown or knockout of YTHDC1 played an opposite effect. Mechanistically, E2 promoted YTHDC1 expression through retinoid X receptor alpha (RXRA) upregulation. YTHDC1 could activate WNT and JAK/STAT signaling pathways in the human trophoblast cells. Meanwhile, YTHDC1 could fine-tone the translation of ribosomal protein L37 (RPL37) in a m6A-dependent manner, which then influence the cellular total protein synthesis. Importantly, administration of siRNA targeting YTHDC1 effectively delays preterm birth in vivo. Collectively, these findings uncover the epigenetic mechanism underlying ART preterm birth and provide a potential target for therapeutic intervention.
2024-09-30 | GSE244402 | GEO
Project description:Antiretroviral therapy (ART) during pregnancy is essential to prevent vertical HIV transmission and preserve the health of the mother and child. However, ART in pregnancy has been associated with adverse birth outcomes linked to poor placental development. Immune dysregulation of placental development is an important factor in the development of pre-eclampsia (PE), a common hypertension disorder of pregnancy. Some studies found an association between ART use at conception or during the first trimester and PE. To investigate the immune environment in pregnant persons with HIV (PPWH) on ART at conception (N=40) compared to PPWH that started ART in the 2nd trimester (N=40) we analyzed data from the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Perinatal Core Protocol, P1025, concluded in 2013. No difference was found in soluble factors in circulation including PlGF and sFLt-1, associated with PE. However, upon analysis of PBMC by high dimension flow cytometry, we detected a lower frequency of circulating CD49a+ NK cells, associated with uterine tissue and pregnancy, in PPWH on ART at conception compared with PPWH who started ART in the 2nd trimester. Moreover, PBMC from PPWH on ART at conception expressed higher levels of SERPINB2 in transcriptomics analyses. Our findings shed new insights into the potential impact of ART at conception and suggest the persistence of a dysregulated inflammatory environment compared to PPWH starting ART after the conclusion of placental development.
2025-06-01 | GSE275120 | GEO
Project description:Assisted reproductive technology (ART) pregnancies present a higher risk of singleton preterm birth than natural pregnancies, but the underlying molecular mechanism remains largely unknown. RNA m6A modification is a key epigenetic mechanism regulating cellular function, but the role of m6A modification, especially its "reader" YTHDC1, in preterm delivery remains undefined. To delineate the role and epigenetic mechanism of m6A modification in ART preterm delivery, the effects of YTHDC1 on trophoblastic function were evaluated by CCK-8, EdU, Transwell, and flow cytometry analyses post its overexpression or knockdown. Downstream signaling pathways of YTHDC1 were investigated by RNA-seq, and targeted mRNAs were explored by RIP-seq and MeRIP-seq. Upstream transcriptional factors of YTHDC1 were determined by ChIP-seq and luciferase reporter assays. Elevated YTHDC1 was detected in human ART-conceived preterm placentas and in murine preterm placentas post estradiol (E2) exposure. In vitro experiments showed that YTHDC1 promoted trophoblastic cell proliferation and migration, but inhibited cell apoptosis. Mechanistically, E2 was proven to upregulate YTHDC1 expression via retinoid X receptor alpha (RXRA) in trophoblastic cells. Enhanced YTHDC1 expression augmented the translation of RPL37 in an m6A-dependent manner by binding to m6A-modified RPL37 mRNA and concomitantly promoted the overall translational output. Importantly, administration of siRNA targeting YTHDC1 effectively delayed the progression of preterm delivery. In conclusion, the identified E2/RXRA/YTHDC1/RPL37 axis provides new insights into the epigenetic mechanism underlying ART-associated preterm delivery. The findings offer a potential prognostic biomarker and therapeutic target for preterm delivery.
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Project description:X-linked inhibitor of apoptosis protein (XIAP), a member of the IAP family, is overexpressed in a variety of tumors and plays an important role in tumor progression. Increasing evidence suggests that XIAP promotes metastasis of bladder cancer but the underlying mechanism is not very clear. The RNA N6-methyladenosine (m6A) reader YTHDC1 regulates RNA splicing, nuclear transport, and mRNA stability and is a potential tumor target; however, its ubiquitin E3 ligase has not been described. In this study, screening of proteins that specifically interact with XIAP identified YTHDC1 to be its degradation substrate. Ectopic overexpression of XIAP promoted degradation of YTHDC1, and knockout of XIAP upregulated YTHDC1, which inhibited metastasis of bladder cancer. Furthermore, YTHDC1 reduced expression of matrix metalloproteinase-2 (MMP-2) by destabilizing its mRNA. These experiments revealed that XIAP promotes ubiquitination of YTHDC1, positively regulating expression of MMP-2 and promoting metastasis of bladder cancer. Collectively, these findings demonstrate that XIAP is a critical regulator of YTHDC1 and pinpoint the XIAP/YTHDC1/MMP-2 axis as a promising target for the treatment of bladder cancer.
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Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae
2016-08-21 | GSE69996 | GEO
Project description:The human placenta is covered by a single multinucleated fetal cell, the syncytiotrophoblast, which is bathed in maternal blood. During all pregnancies, membrane enclosed extracellular vesicles derived from the syncytiotrophoblast are extruded into the maternal blood.The large size of these extracellular vesicles (diameter larger than 10µm) is referred to as trophoblastic debris in this study. We have shown in the past that endothleial cells are involved in clearence of this trophoblastic debris and induction of immune tolerence by trophoblastic debris.This study aimed to characterise the transcriptional changes that occur in human vascular endothelial cells following exposure to trophoblastic debris from normal first trimester placentae. Microarrays were used to probe transcriptomic changes 2 and 21 hours after exposure of endothelial cells (Human microvascular endothelial cell line,HMEC-1) to trophoblastic debris from normal first trimester placentae Trophoblastic debris were isolated by low speed centrifugation from three individual first trimester human placentae (three biological replicates). The protein content in trophoblastic debris was measured by BCA assay. HMEC-1 was co-cultured with trophoblastic debris (60ug/ml total debris protein contents) for either 2 or 21 hours before RNA extraction. Untreated HMEC-1 at 2 and 21 hours were used as controls.In total, 12 samples were analyzed.
2016-08-21 | E-GEOD-69996 | biostudies-arrayexpress
Project description:ART is associated with abnormalities in DNA methylation and a higher incidence of adverse pregnancy outcomes in humans and mice. However, which specific exposure, among the interventions utilized during ART, is responsible for these outcomes remains unknown. Embryo transfer after vitrification-thaw (frozen ET) into a maternal hormonal environment more closely resembling unassisted conception is increasingly utilized clinically, but reports suggest a higher incidence of large for gestational age (LGA) infants, with male infants potentially more affected than female infants.
2022-04-26 | GSE201496 | GEO
Project description:YTHDC1 is one of m6A reader proteins exerting multifaceted effects on determining the fate of m6A RNA within the nucleus.To understand how YTHDC1 contributes to liver cancer progression, we conducted RNA-seq assay in shCtrl and shDC1 HepG2 cells and aimed to identified YTHDC1-responsive genes.
2025-03-25 | E-MTAB-14193 | biostudies-arrayexpress
Project description:Gene expressions obtained from the total RNA sequencing of 2 choriocarcinomas, 4 epithelioid trophoblastic tumors, and 4 placental site trophoblastic tumors were evaluated for differential gene expression, pathway alteration, fusion gene, infiltrating immune cell type, and PD-L1 expression level, and mutation analysis was performed using the RNA sequencing data.
2021-01-04 | GSE135727 | GEO
Project description:Cells have evolved a robust and highly regulated DNA damage response to preserve their genomic integrity. Although increasing evidence highlights the relevance of RNA regulation, our understanding of its impact on a fully efficient DNA damage response remains limited. Here, through a targeted CRISPR-knockout screen, we identified RNA binding proteins and modifiers that participate in mediating the p53 response. Among the top hits, m6A reader YTHDC1 was identified as a master regulator of p53 expression. YTHDC1 binds to the transcription start sites ofTP53and other genes involved in DNA damage response, promoting their transcriptional elongation. YTHDC1 deficiency leads to reducedTP53expression, and also retention of introns leading to aberrant protein production of key DNA damage factors. While intron retention is dependent on m6A, YTHDC1 favoursTP53transcriptionalpause-release independently of m6A. Depletion of YTHDC1 causes genomic instability and aberrant cancer cell proliferation mediated by genes regulated by YTHDC1. Our results uncover YTHDC1 as an orchestrator of the DNA damage response through distinct mechanisms of co-transcriptional mRNA regulation.
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