YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia
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ABSTRACT:
PROVIDER: PRJNA1052693 | ENA |
REPOSITORIES: ENA
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Project description:Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism behind the dysregulation of thrombopoiesis in ITP remains undetermined. In this study, we examined the role of YAP1, Yes-associated protein 1, in thrombopoiesis during ITP. We observed a reduced YAP1 expression with cytoskeletal actin misalignment in MKs of ITP patients. Using experimental ITP mice, we showed that YAP1 reduction induced aberrant MK distribution, reduced the percentage of late MKs in total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by GATA1 binding to its promoter promoted MK maturation. Phosphorylated YAP1 facilitated cytoskeletal activation by binding of its WW2 domain to MYH9, facilitating thrombopoiesis. Targeting YAP1 by its activator XMU-MP-1 was sufficient to rescue cytoskeleton defects and thrombopoiesis in YAP1+/- ITP mice and ITP patients. Taken together, these results demonstrate a crucial role for YAP1 in thrombopoiesis, providing a potential for the development of diagnostic markers and therapeutic options for ITP.
2024-12-22 | GSE250220 | GEO
Project description:Immune thrombocytopenia (ITP) is a complicated bleeding disease characterized by sharp platelet reduction. As a dominating element involved in ITP, megakaryocytes (MKs) are responsible for thrombopoiesis. However, the mechanism behind the dysregulation of thrombopoiesis in ITP remains undetermined. In this study, we examined the role of YAP1, Yes-associated protein 1, in thrombopoiesis during ITP. We observed a reduced YAP1 expression with cytoskeletal actin misalignment in MKs of ITP patients. Using experimental ITP mice, we showed that YAP1 reduction induced aberrant MK distribution, reduced the percentage of late MKs in total MKs, and caused submaximal platelet recovery. Mechanistically, YAP1 upregulation by GATA1 binding to its promoter promoted MK maturation. Phosphorylated YAP1 facilitated cytoskeletal activation by binding of its WW2 domain to MYH9, facilitating thrombopoiesis. Targeting YAP1 by its activator XMU-MP-1 was sufficient to rescue cytoskeleton defects and thrombopoiesis in YAP1+/- ITP mice and ITP patients. Taken together, these results demonstrate a crucial role for YAP1 in thrombopoiesis, providing a potential for the development of diagnostic markers and therapeutic options for ITP.
2024-12-31 | GSE251704 | GEO
Project description:YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia [scRNA-seq]
| PRJNA1055089 | ENA
Project description:Myosin heavy chain 9 (MYH9) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in MYH9 cause an array of autosomal dominant disorders, known as MYH9-related diseases (MYH9-RD). However, the role of MYH9 in normal hematopoiesis remains largely unexplored. By using Mx1-cre Myh9 conditional knockout mice, we established an inducible system to precisely inactivate Myh9 function in hematopoietic cells in vivo. The results showed that deletion of Myh9 led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by Myh9 ablation is cell autonomous. In addition, Myh9 deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Collectively, our findings suggest an essential role for Myh9 in the survival and maintenance of HSPC in normal hematopoiesis.
2022-06-01 | GSE198134 | GEO
Project description:The Hippo pathway effector YAP1 controls stem cell fate in epithelial tissues, but its role in stem cells of non-epithelial tissues, such as skeletal muscle, is poorly documented. Here we show that sustained YAP1 activity in mouse activated satellite cells in vivo induces rhabdomyosarcoma (RMS) resembling human embryonal RMS (ERMS) with high penetrance and short latency. The transcriptional program of YAP1 in ERMS drives pro-proliferative pathways whilst decreasing MyoD1 and MEF2 pro-differentiation activity to globally maintain the myoblastic phenotype of ERMS. Normalization of YAP1 expression reduced tumor burden and allowed myogenic differentiation of YAP1-driven and RD ERMS xenografts in situ, thereby identifying YAP1 as a potent RMS-causing oncogene and potential target for differentiation therapy. A total of four samples were analyzed. Two ChIP-Seq datasets from RD human cells, containing reads connected to TEAD binding and IgG binding as control/background; two ChIP-Seq datasets from YAP-ERMS mouse cells, containing reads connected to TEAD binding and Input reads as control/background
2014-08-12 | E-GEOD-55186 | biostudies-arrayexpress
Project description:Hippo signaling pathway is pivotally involved in human cancer. Among the Hippo components, YAP1 is highly active while function of MST1,2 and SAV1 was lost in liver cancer. Based on systematic analysis, we identified KLF5 as YAP1 binding partner in silico. To investigate KLF5 in liver cancer, we performed the gene expression microarray after knocked down YAP1, TEAD1 and KLF5 in SK-Hep1 cell line. To identify the role of YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line, we performed microarray after knocking down YAP1, TEAD1 and KLF5 in hepatocellular carcinoma cell line (3 siLuc, 3 siYAP1, 3 siTEAD1, 3 siKLF5)
2013-12-31 | E-GEOD-32597 | biostudies-arrayexpress
Project description:YAP1 is a major effector of the Hippo pathway and a well-established oncogene. Elevated YAP1 activity due to mutations in Hippo pathway components or YAP1 amplification is observed in several types of human cancers. Here we investigated its genomic binding landscape in YAP1-activated cancer cells, as well as in non-transformed cells. We demonstrate that TEAD transcription factors mediate YAP1 chromatin-binding genome-wide, further explaining their dominant role as primary mediators of YAP1-transcriptional activity. Moreover, we show that YAP1 largely exerts its transcriptional control via distal enhancers that are marked by H3K27 acetylation and that YAP1 is necessary for this chromatin mark at bound enhancers and the activity of the associated genes. This work establishes YAP1-mediated transcriptional regulation at distal enhancers and provides an expanded set of target genes resulting in a fundamental source to study YAP1 function in a normal and cancer setting.
2015-08-25 | GSE61852 | GEO
Project description:In order to define YAP1-specific gene expression patterns in gastric cancer, the constitutively active mutant YAP1 (YAP1-S127A) was over-expressed in MKN45 gastric cancer cells. Defined gene expression signature was later used to stratify gastric cancer patients according to the presence of the YAP1-activated signature. Three groups of samples are included: 1. Mock control; 2. Vector control; 3. YAP-S127A expression. Gene expression profiles of YAP-S127A mutant-expressing cells were compared to that of mock and vector control. Experiments were done in MKN45 gastric cancer cells.
2013-10-01 | E-GEOD-41387 | biostudies-arrayexpress
Project description:Doxycycline-inducible YAP1 S127A-driven rhabdomyosarcoma (RMS) tumors, control skeletal muscle and regressed tumors following YAP1 normalization by doxycycline withdrawal were compared to determine the YAP1-regulated gene expression profile relevant to RMS formation. To characterize the role of YAP1 in embryonal RMS at the molecular level and identify a gene signature for YAP1 activity readout, we compared the gene expression profiles of our YAP1-driven ERMS with control donor skeletal muscle (SKM) and doxycycline-withdrawn regressing tumors by microarray (doxycycline withdrawal for 3 or 6 days; OFF3 and OFF6, respectively). We next extracted a list of genes regulated by YAP1 in our YAP1-driven ERMS tumors (TUM) versus the 3 other conditions: skeletal muscle control (SKM), Doxycycline-withdrawn 3 days (OFF3) and 6 days (OFF6). The overlap between the 3 lists identified a subset of 633 common upregulated genes, named the YAP1-ERMS_UP signature, as well as 249 common downregulated genes, termed the YAP1-ERMS_DOWN signature. Proliferative pathways and transcriptional targets of E2F factors were highlighted in the YAP1-ERMS_UP genes, while muscle differentiation and trancriptional targets of myogenic factors Myod1 and Mef2 were highlighted in the YAP1-ERMS_DOWN genes. Tumor regression conditions (OFF3 days; OFF6 days) as well as control muscle (CTL) were compared with tumors at day 0 of doxycycline withdrawal (TUM). 3 samples for each conditions were used.
2014-08-12 | E-GEOD-47198 | biostudies-arrayexpress
Project description:Hypertension is a common cardiovascular disease that is related to genetic and environmental factors, but its mechanisms remain unclear. DNA methylation, a classical epigenetic modification, not only regulates gene expression but is also susceptible to environmental factors, linking environmental factors to genetic modification. Therefore, globally screening differential genomic DNA methylation in hypertensive patients is important for investigating novel hypertension mechanisms.Differential genomic DNA methylation in hypertensive, prehypertensive, and healthy control individuals was screened using the Illumina 450K BeadChip and verified by pyrosequencing. Plasma oviduct glycoprotein 1 (OVGP1) levels were determined using an enzyme-linked immunosorbent assay. Ovgp1 transgenic and knockout mice were generated to analyze the function of OVGP1. The blood pressure levels of the mouse models were measured using the tail-cuff system and radiotelemetry methods. The role of OVGP1 in vascular remodeling was determined by vascular relaxation studies. Protein–protein interactions were investigated using a pull-down/mass spectrometry assay and verified with coimmunoprecipitation and pull-down assays. We found a hypomethylated site at cg20823859 in the promoter region of OVGP1, and the plasma OVGP1 levels were significantly increased in hypertensive patients. This finding indicates that OVGP1 is associated with hypertension. In Ovgp1 transgenic mice, OVGP1 overexpression caused an increase in blood pressure, dysfunctional vasoconstriction and vasodilatation, remodeling of arterial walls, and increased vascular superoxide stress and inflammation, and these phenomena were exacerbated by angiotensin II infusion. In contrast, Ovgp1 deficiency attenuated angiotensin II-induced vascular oxidase stress, inflammation, and collagen deposition. These findings indicate that OVGP1 is a prohypertensive factor that directly promotes vascular remodeling. Pull-down and coimmunoprecipitation assays showed that myosin heavy chain II-A (MYH9) interacted with OVGP1, whereas inhibition of MYH9 attenuated OVGP1-induced hypertension and vascular remodeling. CONCLUSIONS: Hypomethylation at cg20823859 in the promoter region of OVGP1 is associated with hypertension and induces upregulation of OVGP1. The interaction between OVGP1 and MYH9 contributes to vascular remodeling and dysfunction. Therefore, OVGP1 is a prohypertensive factor that promotes vascular remodeling by binding with MYH9.
2022-06-12 | GSE205952 | GEO