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1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

ABSTRACT: We identified 1-deoxysphingosine as a ligand for NR2F1 and NR2F2. To prove physiological relevance after in vitro binding assay we used different strategies to manipulate levels of 1-deoxysphingosines and canonical sphingosines in cardiomyocytes derived from human embrynonic stem cells. These manipulations included treating cells with sphingolipid biosynthesis inhibitors (myriocin), adding 1-deoxysphingosines to culture media or induced expression of the Sptlc1 HSAN mutant C133W to enhance 1-deoxysphingosine synthesis by cardiomyocytes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE184913 | GEO | 2021/10/21

REPOSITORIES: GEO

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1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

Project description:We identified 1-deoxysphingosine as a ligand for NR2F1 and NR2F2. To prove physiological relevance after in vitro binding assay we investigated the role of NR2F1 and NR2F2 in cardiomyocyte differentiation. We also used different strategies to manipulate levels of 1-deoxysphingosines and canonical sphingosines in cardiomyocytes derived from human embryonic stem cells. Here we generated both single knockout of NR2F2 and double knockouts of NR2F1 and NR2F2 in human embryonic stem cell line H9. The differentiation of WT, KO and DKO lines into cardiomyocytes was then compared by single-cell RNA-seq analysis.

2021-10-08 | GSE185456 | GEO

Gene expression by myriocin treatment

Project description:Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish this goal are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low-dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes and we showed recently that low-dose myriocin treatment increases yeast lifespan at least in part by down-regulating the sphingolipid-controlled Pkh1/2-Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment has global influences and modulates the evolutionarily conserved Snf1/AMPK, PKA and TORC1 signaling pathways to enhance yeast lifespan. These extensive affects of myriocin rival those of rapamycin and calorie restriction. Our studies in yeast along with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age-related diseases in humans. No-myriocin-treated cells and myriocin-treated cells; three biological replicates in each treatment

2014-09-22 | E-GEOD-41362 | biostudies-arrayexpress

Atrial Identity Is Determined by A COUP-TFII Regulatory Network (ChIP-Seq)

Project description:Embryonic cardiomyocytes possess the plasticity to choose between atrial and ventricular fates. For a limited window of time, the transcription factor COUP-TFII (Nr2f2) sufficiently and essentially confers the atrial identity through direct and indirect regulation of nearly half of chamber specific genes. Examination of COUP-TFII binding sites in embryonic artia

2013-06-07 | E-GEOD-46497 | biostudies-arrayexpress

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development.

Project description:Identification of physiological modulators of nuclear hormone receptor (NHR) activity is paramount for understanding the link between metabolism and transcriptional networks that orchestrate development and cellular physiology. Using libraries of metabolic enzymes alongside their substrates and products, we identify 1-deoxysphingosines as modulators of the activity of NR2F1 and 2 (COUP-TFs), which are orphan NHRs that are critical for development of the nervous system, heart, veins, and lymphatic vessels. We show that these non-canonical alanine-based sphingolipids bind to the NR2F1/2 ligand-binding domains (LBDs) and modulate their transcriptional activity in cell-based assays at physiological concentrations. Furthermore, inhibition of sphingolipid biosynthesis phenocopies NR2F1/2 deficiency in endothelium and cardiomyocytes, and increases in 1-deoxysphingosine levels activate NR2F1/2-dependent differentiation programs. Our findings suggest that 1-deoxysphingosines are physiological regulators of NR2F1/2-mediated transcription.

| S-EPMC8628544 | biostudies-literature

Atrial Identity Is Determined by A COUP-TFII Regulatory Network (ChIP-Seq)

2013-06-07 | GSE46497 | GEO

Gene expression by myriocin treatment

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Effect of deletion of SPTLC1 on gene expression and differentiation of mouse Th17 cells in vitro

Project description:Th17 cells are implicated in autoimmune diseases and several metabolic processes are shown to be important for their development and function. However, the role of de novo sphingolipid biosynthesis in their differentiation and function is less known. To investigate the role of SPTLC1(major subunit of serine palmitoyl transferase enzyme (SPT) that catalyzes the first and rate limiting step of de novo sphingolipid synthesis) in mouse Th17 cell differentiation, we have activated the WT and SPTLC1 defecient (KO) naïve CD4+ T cells, isolated from mouse spleen and lymph nodes, in Th17 differentiating condition in the precence and absence of NAC ( N-acetyl cysteine) and 3-KDS (3-ketodihydrosphingosine).

2024-03-21 | GSE254602 | GEO

Genome-wide analysis of p300, H3K4me3, H3K4me1, H3K27me3 and H3K27ac in in vitro differentiated human neural crest cells (hNCC)

Project description:Combining an in vitro hNCC differentiation protocol with epigenomic profiling, we provide the first whole-genome characterization of cis-regulatory elements in this highly relevant cell type. With this data at hand, we have characterized the chromatin state and dynamics of all human gene promoters during the course of NCC in vitro differentiation. Most importantly, we have identified a large cohort of active and NCC-specific enhancers, which we showed to be functionally relevant in vivo, in the context of embryonic development. Finally, through sequence analysis of the identified NCC enhancers, we uncovered the orphan nuclear receptors NR2F1 and NR2F2 as novel hNCC transcriptional regulators both in vitro and in vivo. Genome-wide analysis of p300, H3K4me3, H3K4me1, H3K27me3, H3K27ac, NR2F1, NR2F2 and TFAP2A in in vitro differentiated human neural crest cells (hNCC)

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Genome-wide CRISPRi screen for myriocin sensitivity

Project description:To delineate cellular pathways underlying cell growth in the absence of sphingolipid syntehsis, we performed a genome-wide CRISPRi screen to identify genetic modifiers of myriocin sensitivity in human K562 cells.

2020-07-09 | GSE154045 | GEO

RNA-seq analysis of S16 Schwann cells treated with siRNA for Nr2f1/Nr2f2 (CoupTFI/CoupTFII)

Project description:In a previous study, we had compared SOX10-bound regulatory elements in Schwann cells and oligodendrocytes, and we identified a specific enrichment for nuclear receptor motifs at SOX10 binding sites in Schwann cells. We initially focused on NR2F1 and NR2F2 (CoupTF1/CoupTF2) since they are expressed from neural crest through Schwann cell maturity, and found that knockdown of nuclear receptors Nr2f1 and Nr2f2 in primary Schwann cells downregulated genes such as Myelin Basic Protein (Mbp) and Desert Hedgehog (Dhh). In this study, we have elucidated a NR2F-regulated target gene network in Schwann cells, which revealed enrichment for non-myelinating Schwann cell genes. Cut&Run assays in S16 Schwann cells revealed novel, genome-wide binding sites of NR2F1/2 and downstream transcription factors, Retinoid X Receptor (RXRG) and TEA-Domain factor (TEAD1).

2024-02-01 | GSE252428 | GEO

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