NLRP7 maintains the genomic stability during early human embryogenesis via mediating alternative splicing
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PROVIDER: PRJNA1185654 | ENA |
REPOSITORIES: ENA
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Project description:Genomic instability is the main cause of abnormal embryo development and abortion. NLRP7 dysfunctions affect embryonic development and lead to recurrent pregnancy loss (RPL) or hydatidiform moles (HM), but the underlying mechanisms remain largely elusive. In this study, we found that NLRP7 knockout affected the genetic stability, resulting in increased DNA damage in both human embryonic stem cells (hESCs) and blastoids, making embryonic cells in blastoids more susceptible to apoptosis. Mechanistically, NLRP7 could interact with factors related to alternative splicing (AS) and DNA damage response (DDR), including DDX39B, PRPF8, THRAP3 and PARP1, and its dysfunction led to abnormal AS of genes involved in Homologous recombination (HR) in hESCs, indicating that NLRP7-mediated AS is required for the maintenance of genome integrity during early human embryogenesis. Together, this study first uncovers that NLRP7 plays an essential role in the maintenance of genetic stability during early human embryonic development by regulating AS of HR-related genes.
2025-01-16 | GSE281755 | GEO
Project description:The protection of UCK2 protein stability by GART maintains pyrimidine salvage synthesis for HCC growth under glucose limitation
2024-10-22 | PXD057046 |
Project description:ObjectiveIn this study, we generated an Rbm14 knockout mouse model to explore its functions during early mouse embryogenesis.Materials and methodsThe Rbm14 knockout mouse model was generated by a combination of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and microinjection techniques. The developmental defects of the knockout embryos were characterized by histological analyses. The accumulation of DNA damage in mouse embryonic stem cells (ESCs) was detected by ?H2AX staining and comet assay. The altered mRNA splicing of DNA damage response (DDR)-related genes was detected by RNA-Seq analysis and confirmed by semi-quantitative PCR. The interaction of RBM14 with alternative splicing-related genes was detected by immunoprecipitation-mass spectra (IP-MS) and confirmed by co-immunoprecipitation (Co-IP).ResultsRbm14 knockout in mice results in apoptosis and cell proliferation defects in early post-implantation epiblast cells, leading to gastrulation disruption and embryonic lethality. FACS and immunostaining demonstrate accumulation of DNA damage in Rbm14 knockout ES cells. We also identified altered splicing of DDR-related genes in the knockout mouse ESCs by RNA-Seq, indicating that RBM14-mediated alternative splicing is required for the maintenance of genome integrity during early mouse embryogenesis.ConclusionsOur work reveals that Rbm14 plays an essential role in the maintenance of genome integrity during early mouse embryonic development by regulating alternative splicing of DDR-related genes.
| S-EPMC6985654 | biostudies-literature
Project description:Genomic instability is the main cause of abnormal embryo development and abortion. NLRP7 dysfunctions affect embryonic development and lead to Hydatidiform Moles, but the underlying mechanisms remain largely elusive. Here, we show that NLRP7 knockout affects the genetic stability, resulting in increased DNA damage in both human embryonic stem cells and blastoids, making embryonic cells in blastoids more susceptible to apoptosis. Mechanistically, NLRP7 can interact with factors related to alternative splicing and DNA damage response, including DDX39B, PRPF8, THRAP3 and PARP1. Moreover, NLRP7 dysfunction leads to abnormal AS of genes involved in Homologous recombination in human embryonic stem cells, Such as Brca1 and Rad51. These results indicate that NLRP7-mediated Alternative splicing is potentially required for the maintenance of genome integrity during early human embryogenesis. Together, this study uncovers that NLRP7 plays an essential role in the maintenance of genetic stability during early human embryonic development by regulating alternative splicing of Homologous Recombination-related genes.
2025-01-17 | PXD059649 | Pride
Project description:Leptin signaling maintains autonomic stability during severe influenza infection
| PRJNA1147219 | ENA
Project description:UFMylation maintains YAP stability to promote vascular endothelial cell senescence
| PRJNA1143423 | ENA
Project description:The Tumor Suppressor Hic1 Maintains Chromosomal Stability Independent of Tp53
| PRJNA412520 | ENA
Project description:Complete Hydatidiform Mole (HM) is a gestational trophoblastic disease resulting in hyper proliferation of trophoblast cells and absence of embryo development. Mutations in NLRP7 gene is a major cause of familial recurrent complete HM, where no embryonic tissue is present during the pregnancy. NLRP7 is a novel protein and its function is poorly understood. Lack of NLRP7 in the mouse genome and challenges in studying human embryogenesis as well as human trophoblast differentiation has prevented elucidation of the pathophysiology of this disease and the function of NLRP7 in HM. Here, we established an in vitro model of HM using NLRP7 deficient patient-derived human induced pluripotent stem cells (iPSCs). Whole transcriptome profiling during trophoblast differentiation revealed that NLRP7 deficiency results in precocious downregulation of pluripotency factors, activation of trophoblast genes and promotes maturation of differentiated extraembryonic cell types such as syncytiotrophoblasts. We further showed that these phenotypes are dependent on BMP4 signaling and BMP pathway inhibition prevented excessive trophoblast differentiation of HM-iPSCs. Taken together, this novel human iPSC model of a genetic placental disease recapitulates aspect of trophoblast biology and sheds light on early human embryogenesis by identifying NLRP7 as an important regulator of this process.
2021-09-09 | GSE125592 | GEO
Project description:Endothelial cell senescence is an accomplice for vascular aging, which leads to cardiovascular diseases (CVD). Evidences showed that Hippo- Yes-associated protein (YAP) signaling pathway plays an essential role in aging-associated CVD. However, the exact role of YAP protein in endothelial cell senescence remains not fully clear. Here, we reported that YAP was elevated in senescent human umbilical vein endothelial cells (HUVECs) and inhibition of YAP by either specific siRNAs or inhibitor Verteporfin could attenuate HUVECs senescence. In contrast, overexpression of YAP induces cell senescence. Besides, we found that UFMylation activity and YAP were both elevated in senescent cells. Mechanistically, we found that UFMylation, a newly identified ubiquitin-like modification with essential biological functions, maintains the stability of YAP and further found that YAP is a substrate for UFMylation. Importantly, we found that compound 8.5, an inhibitor of E1 of UFMylation, can attenuate cell senescence with reduced YAP protein and alleviate vascular aging and improve cardiac function in aged mice. Therefore, compound 8.5 may be a potential small molecule for delaying vascular aging. Together, our finding provides molecular mechanism by which UFMylation maintains YAP stability and exerts an important role in promoting cell senescence, and identified that a previously unrecognized UFMylation is a potential therapeutic target for anti-aging.
2025-01-08 | GSE273828 | GEO
Project description:PHF2 maintains neural progenitor genome stability by preserving pericentric heterochromatin integrity
| PRJNA1013331 | ENA