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Epigenetic Landscape Reveals MECOM As An Endothelial Lineage Regulator

ABSTRACT: Epigenetic Landscape Reveals MECOM As An Endothelial Lineage Regulator

PROVIDER: PRJNA673857 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12965718_1.fastq.gz	Fastqsanger.gz
	SRR12965718_2.fastq.gz	Fastqsanger.gz
	SRR12965719_1.fastq.gz	Fastqsanger.gz
	SRR12965719_2.fastq.gz	Fastqsanger.gz
	SRR12965720_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Epigenetic Landscape Reveals MECOM As An Endothelial Lineage Regulator

Project description:Background: A comprehensive understanding of the determinants of endothelial cell (EC) lineage specification will advance strategies for cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures specifically regulate cell identity genes, making it possible to systematically identify novel EC master regulators by leveraging extensive epigenomic datasets available for EC. Methods: We developed a method to identify novel regulators of endothelial cell identity by integrating multiple epigenetic patterns. We verified MEOCM as a master EC lineage regulator using both in vivo and in vitro experiments. The mechanism of action of MECOM as EC lineage regulator was characterized by integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, scRNA-seq and bulk RNA-Seq data, as well as extensive molecular, cellular, and animal experiments. Results: We identified MECOM to be the leading candidate as an EC lineage regulator. Single-cell RNA-Seq analysis further revealed that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide iPSC-ECs. We verified that MECOM was required for human endothelial differentiation, EC functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate EC identity genes. Specifically, we identified the VEGF signaling pathway to be a key downstream target of MECOM. Conclusions: Our work provides new insights into epigenetic regulation of cell identity genes and uncovered MECOM as a master regulator of EC identity.

2023-03-16 | GSE160647 | GEO

Epigenetic landscape reveals MECOM as an endothelial lineage regulator.

Project description:A comprehensive understanding of endothelial cell lineage specification will advance cardiovascular regenerative medicine. Recent studies found that unique epigenetic signatures preferentially regulate cell identity genes. We thus systematically investigate the epigenetic landscape of endothelial cell lineage and identify MECOM to be the leading candidate as an endothelial cell lineage regulator. Single-cell RNA-Seq analysis verifies that MECOM-positive cells are exclusively enriched in the cell cluster of bona fide endothelial cells derived from induced pluripotent stem cells. Our experiments demonstrate that MECOM depletion impairs human endothelial cell differentiation, functions, and Zebrafish angiogenesis. Through integrative analysis of Hi-C, DNase-Seq, ChIP-Seq, and RNA-Seq data, we find MECOM binds enhancers that form chromatin loops to regulate endothelial cell identity genes. Further, we identify and verify the VEGF signaling pathway to be a key target of MECOM. Our work provides important insights into epigenetic regulation of cell identity and uncovered MECOM as an endothelial cell lineage regulator.

| S-EPMC10130150 | biostudies-literature

Mapping the developing human cardiac endothelium at single cell resolution identifies MECOM as a regulator of arteriovenous identity.

Project description:Aims: Coronary vasculature formation is a critical event during cardiac development, essential for heart function throughout perinatal and adult life. However, current understanding of coronary vascular development has largely been derived from transgenic mouse models. The aim of this study was to characterise the transcriptome of the human fetal cardiac endothelium using single-cell RNA sequencing (scRNA-seq) to provide critical new insights into the cellular heterogeneity and transcriptional dynamics that underpin endothelial specification within the vasculature of the developing heart. Methods and Results: We acquired scRNA-seq data of over 10,000 fetal cardiac endothelial cells (EC), revealing divergent EC subtypes including endocardial, capillary, venous, arterial, and lymphatic populations. Gene regulatory network analyses predicted roles for SMAD1 and MECOM in determining the identity of capillary and arterial populations, respectively. Trajectory inference analysis suggested an endocardial contribution to the coronary vasculature and subsequent arterialisation of capillary endothelium accompanied by increasing MECOM expression. Comparative analysis of equivalent data from murine cardiac development demonstrated that transcriptional signatures defining endothelial subpopulations are largely conserved between human and mouse. Furthermore, we revealed that knockdown of MECOM in human embryonic stem cell-derived EC (hESC-EC) resulted in an increase in venous EC marker expression, validating our prediction of its role in arterial EC identity. Conclusions: scRNA-seq of the human fetal cardiac endothelium identified distinct EC populations. A predicted endocardial contribution to the developing coronary vasculature was identified, as well as subsequent arterial specification of capillary EC. Loss of MECOM in hESC-EC increased venous EC marker expression, suggesting a role in maintaining arterial EC identity.

2022-03-02 | GSE195911 | GEO

Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification

Project description:This SuperSeries is composed of the following subset Series: GSE40684: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [ChIP-Seq] GSE40685: Foxp3 exploits a preexistent enhancer landscape for regulatory T cell lineage specification [Expression] Refer to individual Series

2012-09-28 | E-GEOD-40686 | biostudies-arrayexpress

SND1 is a novel regulator of endothelial function

Project description:SND1 is a novel regulator of endothelial function

| PRJNA907374 | ENA

A novel microprotein HDSP encoded by HOXA10-HOXA9 triggers progression of gastric cancer through maintaining the stability of MECOM and activating MECOM /SPINK1-/EGFR signaling

Project description:The presence of noncanonical open reading frames within lncRNAs suggests their potential for translation, yielding various functional peptides or proteins. However, the existence and specific roles of these products in gastric cancer remain largely unexplored. Here we identify the HOXA10-HOXA9-derived small protein (HDSP) in gastric cancer through comprehensive analysis and experimental validation, including mass spectrometry and western blotting. HDSP exhibits high expression and oncogenic roles in gastric cancer. Mechanistically, HDSP blocks TRIM25-mediated ubiquitination and degradation by interacting with MECOM, leading to MECOM accumulation and enhanced SPINK1 transcription-a gene promoting cancer via the EGFR signaling pathway. Furthermore, MECOM fosters HOXA10-HOXA9 transcription, establishing a feedback loop activating SPINK1-EGFR signaling. HDSP knockdown inhibits tumor growth in a PDX model, and infusion of an artificially synthesized HDSP peptide as a neoantigen enhances immune cell-mediated anti-tumor efficacy against gastric cancer in vitro and in vivo. These findings propose HDSP as a potential therapeutic target or neoantigen candidate for gastric cancer treatment.

2024-06-18 | PXD053200 | Pride

The lineage-specific transcriptional regulator, CDX2, navigates a dynamic chromatin landscape to control distinct stages of intestinal development

Project description:The lineage-specific transcriptional regulator, CDX2, navigates a dynamic chromatin landscape to control distinct stages of intestinal development

| PRJNA474516 | ENA

Lineage-Specific TOP2A Cleavage Landscape in Leukemia Cell

Project description:Lineage-Specific TOP2A Cleavage Landscape in Leukemia Cell

| PRJNA412503 | ENA

Mapping the developing human cardiac endothelium at single cell resolution identifies MECOM as a regulator of arteriovenous identity.

Project description:Mapping the developing human cardiac endothelium at single cell resolution identifies MECOM as a regulator of arteriovenous identity.

| PRJNA802650 | ENA

The neuronal homeobox transcription factor HMX3 is a crucial vulnerability in MECOM-negative KMT2A::MLLT3 acute myelomonocytic leukemia [RNAseq_MOLM13_HMX3_KD]

Project description:The KMT2A::MLLT3 fusion protein causes acute myeloid leukemia (AML) by activating the oncogenic transcription factor MECOM. However, MECOM expression occurs only in half of the cases. By integrating gene expression and enhancer activity data from patient cells, we identified neuronal homeobox transcription factor HMX3 as cell fate determining factor in MECOM-negative KMT2A::MLLT3 AML. HMX3 expression associated with younger age and KMT2A-rearranged leukemia in large AML cohorts (p<0.002). It was absent in other major genetic risk groups and healthy blood cells. Transcriptomic analyses revealed that HMX3 drives cancer-associated E2F, MYC, and cell cycle gene programs. Ectopic HMX3 expression completely inhibited monocytic but not granulocytic colony formation of healthy CD34+ cord blood cells. Its silencing in KMT2A::MLLT3 AML cell lines and patient cells resulted in cell cycle arrest, monocytic differentiation, and apoptosis. Thus, HMX3 is a leukemia-specific vulnerability that enhances proliferation and blocks differentiation of MECOM-negative KMT2A::MLLT3 leukemia.

2024-12-13 | GSE242962 | GEO

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