Lymphatic-specific Methyltransferase3-mediated m6A modification drives vascular patterning through prostaglandin metabolism reprogramming
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ABSTRACT:
PROVIDER: PRJNA1144117 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30126205_1.fastq.gz | Fastqsanger.gz | |||
| SRR30126205_2.fastq.gz | Fastqsanger.gz | |||
| SRR30126206_1.fastq.gz | Fastqsanger.gz | |||
| SRR30126206_2.fastq.gz | Fastqsanger.gz | |||
| SRR30126207_1.fastq.gz | Fastqsanger.gz |
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Project description:Lymphangiogenesis plays a pivotal role in the pathogenesis of various vascular disorders, including ocular vascular diseases and cancers. Deregulation of N6-methyladenosine (m6A) modification has been identified as a key contributor to human diseases. However, the specific involvement of m6A modification in lymphatic remodeling remains poorly understood. In this study, we demonstrate that inflammatory stimulation and corneal sutures induce elevated levels of METTL3-mediated m6A modification. METTL3 knockdown inhibits lymphatic endothelial viability, proliferation, migration, and tube formation in vitro. METTL3 knockdown attenuates corneal sutures-induced lymphangiogenesis and intratumoral lymphangiogenesis initiated by subcutaneous grafts, consequently restraining corneal neovascularization, tumor growth, and tumor neovascularization in vivo. Mechanistically, METTL3 knockdown upregulates prostaglandin-endoperoxide synthase 2 (PTGS2) expression through an m6A-YTHDF2-dependent pathway, enhancing the synthesis of cyclopentenone prostaglandins (CyPGs). Aberrant CyPG production in lymphatic endothelial cells impairs mitochondrial oxidative phosphorylation, contributing to pathological lymphangiogenesis. Moreover, selective inhibition of METTL3 with STM2457 reduces m6A levels in lymphatic endothelial cells, effectively suppressing pathological lymphangiogenesis. This study provides compelling evidence that lymphatic-specific METTL3 plays a critical role in vascular patterning through prostaglandin metabolism reprogramming. Thus, METTL3 emerges as a promising target for treating pathological lymphangiogenesis.
2024-10-15 | GSE273930 | GEO
Project description:The lymphatic vascular system plays important roles in the maintenance of interstitial fluid pressure, the afferent immune response and the absorption of dietary lipids. However, the molecular mechanisms that control lymphatic vessel network maturation and function remain largely unknown. To identify novel players in lymphatic vessel function, we isolated pure populations of lymphatic and blood vascular endothelial cells from mouse intestine using fluorescence-activated high-speed cell sorting and performed transcriptional profiling. We found that the axonal guidance molecules semaphorin 3A (Sema3A) and Sema3D were specifically expressed by lymphatic vessels. Quantitative PCR of ex vivo isolated cells and immunohistochemical analysis confirmed these results. Importantly, we found that the semaphorin receptor neuropilin-1 (Nrp-1) is expressed on the valves of collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1, but not with an antibody that blocks VEGFA binding to Nrp-1, resulted in abnormal development of collecting lymphatic vessels and valves, and aberrant smooth muscle cell coverage. Conversely, Sema3A-deficient mice displayed branching defects of collecting lymphatic vessels as well as impaired valve development. Together, these results reveal an unanticipated role of Sema3A/Nrp-1 signaling in the maturation of the lymphatic vascular network. Colon single-cell suspensions were prepared by a fast protocol that minimizes the RNA degradation. Fluorescence-activated cell sorting (FACS) was used to sort blood vascular endothelial cells (BEC) and lymphatic endothelial cells (LEC). 4 animal-matched pairs of LEC and BEC were chosen based on the quality of extracted and amplified material to provide homogenous groups of biological replicates. This gave 8 samples to analyze. Samples present LEC and BEC isolated from 4 healthy normal mice. The 4 mice used present the 4 biological replicates.
2012-06-15 | E-GEOD-22034 | biostudies-arrayexpress
Project description:Muraro2014 - Vascular patterning in Arabidopsis roots
Using a multicellular model, maintanence of vascular patterning in Arabidopsis roots has been studied. The model that is provided here is the single-cell version of the model. The two-cell and multicellular models described in the paper can be downloaded as python scripts (follow the curation tab to get these files).
This model is described in the article:
Integration of hormonal signaling networks and mobile microRNAs is required for vascular patterning in Arabidopsis roots.
Muraro D, Mellor N, Pound MP, Help H, Lucas M, Chopard J, Byrne HM, Godin C, Hodgman TC, King JR, Pridmore TP, Helariutta Y, Bennett MJ, Bishopp A.
Proc Natl Acad Sci U S A. 2014 Jan 14;111(2):857-62.
Abstract:
As multicellular organisms grow, positional information is continually needed to regulate the pattern in which cells are arranged. In the Arabidopsis root, most cell types are organized in a radially symmetric pattern; however, a symmetry-breaking event generates bisymmetric auxin and cytokinin signaling domains in the stele. Bidirectional cross-talk between the stele and the surrounding tissues involving a mobile transcription factor, SHORT ROOT (SHR), and mobile microRNA species also determines vascular pattern, but it is currently unclear how these signals integrate. We use a multicellular model to determine a minimal set of components necessary for maintaining a stable vascular pattern. Simulations perturbing the signaling network show that, in addition to the mutually inhibitory interaction between auxin and cytokinin, signaling through SHR, microRNA165/6, and PHABULOSA is required to maintain a stable bisymmetric pattern. We have verified this prediction by observing loss of bisymmetry in shr mutants. The model reveals the importance of several features of the network, namely the mutual degradation of microRNA165/6 and PHABULOSA and the existence of an additional negative regulator of cytokinin signaling. These components form a plausible mechanism capable of patterning vascular tissues in the absence of positional inputs provided by the transport of hormones from the shoot.
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2024-09-02 | BIOMD0000000522 | BioModels
Project description:Precise vascular patterning is critical for normal growth and development. The ERG transcription factor drives Delta like ligand 4 (DLL4)/Notch signalling and is thought to act as pivotal regulators of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC specific Focal Adhesion Kinase (FAK)-knockout (KO) and point-mutant FAK-knockin mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid Immunoprecipitation Mass Spectrometry of Endogenous Proteins identified that endothelial nuclear-FAK interacts with the de-ubiquitinase USP9x and the ubiquitin ligase TRIM25 enzymes. Further in silico analysis corroborates that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x.
2022-07-05 | PXD033447 | Pride
Project description:The lymphatic vascular system plays important roles in the maintenance of interstitial fluid pressure, the afferent immune response and the absorption of dietary lipids. However, the molecular mechanisms that control lymphatic vessel network maturation and function remain largely unknown. To identify novel players in lymphatic vessel function, we isolated pure populations of lymphatic and blood vascular endothelial cells from mouse intestine using fluorescence-activated high-speed cell sorting and performed transcriptional profiling. We found that the axonal guidance molecules semaphorin 3A (Sema3A) and Sema3D were specifically expressed by lymphatic vessels. Quantitative PCR of ex vivo isolated cells and immunohistochemical analysis confirmed these results. Importantly, we found that the semaphorin receptor neuropilin-1 (Nrp-1) is expressed on the valves of collecting lymphatic vessels. Treatment of mice in utero (E12.5-E16.5) with an antibody that blocks Sema3A binding to Nrp-1, but not with an antibody that blocks VEGFA binding to Nrp-1, resulted in abnormal development of collecting lymphatic vessels and valves, and aberrant smooth muscle cell coverage. Conversely, Sema3A-deficient mice displayed branching defects of collecting lymphatic vessels as well as impaired valve development. Together, these results reveal an unanticipated role of Sema3A/Nrp-1 signaling in the maturation of the lymphatic vascular network.
2012-06-16 | GSE22034 | GEO
Project description:The molecular mechanisms that control the ordered patterning of vascular tissue development in plant are not well understood. Several models propose a two component for plant vascular differentiation in which requires both an inducer of vascular tissue an also an inhibitory component that prevents the formation of vascular bundles near pre-existing bundles by a process often termed lateral inhibition. We have identified two recessive allelic mutants in Arabidopsis, designated continuous vascular (cov-1, cov-2), which display a dramatic increase in vascular tissue in the stem in place of the interfascicular region that normally separates the vascular bundles. The mutant plants exhibited normal vascular patterning in leaves and cotyledons. Analysis of the interaction of cov with known auxin signalling mutant and direct analysis of auxin concentrations suggests that cov affects vascular pattering by some mechanism that is independent of auxin. COV is expressed in all plant tissue but more highly in developing flowers and stems. The COV protein is predicted to be an integral membrane protein of unknown function, conserved in both plants and bacteria that is involved in negatively regulating the differentiation of the vascular tissue in the stem of Arabidopsis.The phenotype of COV exhibits some similarities to acl5 which is known to be a defect in the gene for spermidine synthase. Consequently, we are interested to test the idea that COV may be involved in the transport or perception of polyamines and that polyamines may be essential signals in normal vascular tissue development. Clearly, it this proves to be the case we would expect to see some differences in the transcript levels of genes associated with these pathways. Experimenter name = Simon Turner Experimenter phone = 0161 275 5751 Experimenter fax = 0161 275 3938 Experimenter address = University of Manchester Experimenter address = School of Biological Sciences Experimenter address = 3.614 Stopford building Experimenter address = Oxford Rd Experimenter address = Manchester Experimenter zip/postal_code = M13 9PT Experimenter country = UK Keywords: genetic_modification_design
2007-01-08 | GSE5729 | GEO
Project description:The molecular mechanisms that control the ordered patterning of vascular tissue development in plant are not well understood. Several models propose a two component for plant vascular differentiation in which requires both an inducer of vascular tissue an also an inhibitory component that prevents the formation of vascular bundles near pre-existing bundles by a process often termed lateral inhibition. We have identified two recessive allelic mutants in Arabidopsis, designated continuous vascular (cov-1, cov-2), which display a dramatic increase in vascular tissue in the stem in place of the interfascicular region that normally separates the vascular bundles. The mutant plants exhibited normal vascular patterning in leaves and cotyledons. Analysis of the interaction of cov with known auxin signalling mutant and direct analysis of auxin concentrations suggests that cov affects vascular pattering by some mechanism that is independent of auxin. COV is expressed in all plant tissue but more highly in developing flowers and stems. The COV protein is predicted to be an integral membrane protein of unknown function, conserved in both plants and bacteria that is involved in negatively regulating the differentiation of the vascular tissue in the stem of Arabidopsis.The phenotype of COV exhibits some similarities to acl5 which is known to be a defect in the gene for spermidine synthase. Consequently, we are interested to test the idea that COV may be involved in the transport or perception of polyamines and that polyamines may be essential signals in normal vascular tissue development. Clearly, it this proves to be the case we would expect to see some differences in the transcript levels of genes associated with these pathways. Experimenter name = Simon Turner; Experimenter phone = 0161 275 5751; Experimenter fax = 0161 275 3938; Experimenter address = University of Manchester; Experimenter address = School of Biological Sciences; Experimenter address = 3.614 Stopford building; Experimenter address = Oxford Rd; Experimenter address = Manchester; Experimenter zip/postal_code = M13 9PT; Experimenter country = UK Experiment Overall Design: 8 samples were used in this experiment
2008-06-14 | E-GEOD-5729 | biostudies-arrayexpress
Project description:The lymphatic vascular system maintains tissue fluid homeostasis, helps mediate afferent immune responses and promotes cancer metastasis. MicroRNAs (miRNAs) have recently emerged as key and potent regulators of the genome that control virtually all aspects of cell and organism biology. Surprisingly, the physiological importance and functional activities of miRNAs in the lymphatic vascular system have not been explored. To address this, we first defined the in vitro miRNA expression profiles of primary human lymphatic endothelial cells (LECs) and blood vascular endothelial cells (BVECs). Comparative analysis of these profiles identified 4 BVEC-signature and 2 LEC-signature miRNAs. Further expression analysis by quantitative real-time PCR analysis and by in situ hybridization (ISH) studies confirmed these vascular lineage-specific expression patterns in vivo. Functional characterization of the BVEC-signature miRNA, miR-31, identified a novel BVEC-specific post-transcriptional regulatory mechanism that inhibits lymphatic-specific transcription programs in vitro and lymphatic vascular development during Xenopus embryogenesis. These effects are, in part, mediated via direct post-transcriptional repression of PROX1, a master regulator of lymphatic lineage-specific differentiation. Together, these findings indicate that miR-31, and miRNAs in general, are potent regulators of vascular lineage-specific differentiation and development.
2010-06-04 | GSE16908 | GEO
Project description:RhoB null mice show decreases in pathological angiogenesis in the ischemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We used microarrays to link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to RhoB/VEZF1-mediated gene regulation in primary human blood versus lymphatic endothelial cells. Pure populations of human primary BVECs and LVECs silenced for RhoB or VEZF1 were used for RNA extraction and hybridization on Affymetrix microarrays. We extracted these cells from human male foreskins from at least four individuals and purified them using Dynabeads associated with vascular markers (CD31 and Podoplanin).
2013-10-28 | E-GEOD-51754 | biostudies-arrayexpress
Project description:Effect of prostaglandin E2 (PGE2) treatment on human dermal lymphatic endothelial cells (HDLECs)
| PRJNA928677 | ENA