YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia [scRNA-seq]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1055089 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27307063_1.fastq.gz | Fastqsanger.gz | |||
| SRR27307063_2.fastq.gz | Fastqsanger.gz | |||
| SRR27307064_1.fastq.gz | Fastqsanger.gz | |||
| SRR27307064_2.fastq.gz | Fastqsanger.gz | |||
| SRR27307065_1.fastq.gz | Fastqsanger.gz |
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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.
2024-12-31 | GSE251704 | 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.
2024-12-22 | GSE250220 | GEO
Project description:YAP1 regulates thrombopoiesis by binding to MYH9 in immune thrombocytopenia
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Project description:Fate mapping reveals two pathways of native thrombopoiesis (scRNA sequencing)
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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.
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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:The Hippo:YAP1 signaling pathway was long considered a master regulator of organ growth. However, recent evidence has challenged this view, showing that the loss of YAP1 does not prevent several organs from reaching their normal size. Hence, resolving the functions of YAP1 in the embryo has become a central question in the field. To shed light into this, we analyzed YAP1’s role in regulating pluripotency of the mammalian epiblast, using scRNAseq approaches. Conditional deletion of Yap1 in the mouse epiblast (Sox2-Cre) altered the expression of signaling and differentiation genes, including Nodal, Wnt3, Fgf8, and Nanog, without impairing cell proliferation. Instead, Yap1 loss led to hyperactivation of Nodal signaling and enhanced differentiation of the epiblast toward mesodermal fate. Furthermore, an unbiased screening in human pluripotent stem cells revealed that YAP1 transcriptionally cooperates with QSER1 protein, to regulate multiple WNT and NODAL signaling genes. Mechanistically, QSER1 represses lineage enhancers of signaling genes by counteracting RNA Polymerase II recruitment on YAP1-targets. Accordingly, QSER1 depletion, similar to YAP1, leads to hyperactive Nodal signaling in human 2D-gastruloids. Overall, our findings not only advance our understanding of YAP1’s role in early development but also open new avenues for exploring how the interplay with QSER1 could influence additional developmental processes.
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Project description:A Retinoic Acid:YAP1 signaling axis controls atrial lineage commitment [scRNA-seq]
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Project description:Myh9 knockdown reduces the strength of the apical actomyosin cortex from hepatocytes, which causes isotropic growth of the bile canaliculus (BC) and ultimately results in the formation of hepatocyte cysts with a large central apical lumen. Treatment of hepatocytes with the osmotically active bioinert polymer PEG950 causes and increase in intraluminal pressure, which causes expansion of the bile canaliculus (BC) and ultimately results in the formation of hepatocyte cysts with a large central apical lumen. In these cysts, hepatocytes have common apico-basal polarity, such as observed for simple epithelia like cholangiocytes. To investigate whether this change in apical lumen morphology and polarization is associated with alterations in gene expression we compared hepatocytes with and without Myh9 knockdown and with and without PEG950 treatment.
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