SREBP2 regulates endothelial response to inflammation via direct transcriptional activation of KLF6
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA924821 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23101559.fastq.gz | Fastqsanger.gz | |||
| SRR23101560.fastq.gz | Fastqsanger.gz | |||
| SRR23101561.fastq.gz | Fastqsanger.gz | |||
| SRR23101562.fastq.gz | Fastqsanger.gz | |||
| SRR23101563.fastq.gz | Fastqsanger.gz |
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Project description:Cholesterol homeostasis plays a central role in disease pathogenesis in chronic disorders such as cardiovascular and kidney diseases. The transcription factor SREBP2 is the main regulator of cholesterol metabolism and is central to the mechanism of action of lipid lowering drugs, such as statins, that are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic cardiovascular disease. Recently, SREBP2 has been implicated in both the innate and adaptive immune responses by upregulation of cholesterol flux or via direct transcriptional activation of pro-inflammatory genes in leukocytes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and are activated in response to damage and inflammation. The loss of SREBP2 in cultured human ECs results in significant alterations of the transcriptional response to inflammatory cytokines whereas SREBF2 knockdown inhibits the transcription and secretion of pro-inflammatory chemokines but amplifies type I interferon response genes. Furthermore, we show that SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake, but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing (ChIP-seq) of endogenous SREBP2 reveals the SREBP2 bound to the promoter regions of classical response genes as well as two non-classical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. Overexpression of SREBP2 upregulated both BHLHE40 and KLF6 transcripts independent of inflammatory stress and the transcription of these genes were found to be sensitive to cellular cholesterol levels. Of these two targets, we found that KLF6 was responsible for the amplification of chemokine expression highlighting a tight relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.
2023-08-21 | GSE223094 | GEO
Project description:Immunometabolism is a growing field that centers on a core paradigm: perturbations in metabolism alter a cell’s biological response in immunity and, likewise, inflammatory signals, such as cytokines and pathogens, can directly influence cellular metabolism. Although the carbons within cholesterol cannot be used for catabolic energy production, there is a growing appreciation that a similar relationship exists between cholesterol homeostasis and immunity. The majority of this literature is focused on cholesterol dynamics in the context of leukocyte immunobiology. However, the endothelium also plays an important role during the acute inflammatory response. Endothelial cells (ECs) rapidly respond to extrinsic signals, such as tissue damage or microbial infection, by upregulating factors to activate and recruit circulating leukocytes to the site of injury. Dysregulation or aberrant activation of ECs leads to disease, such as atherosclerosis. I studied the role of cholesterol and its master regulator, SREBP2, in the EC response to acute inflammatory stress. ECs treated with cytokines upregulated SREBP2 cleavage and classical cholesterol biosynthesis gene expression within the late phase of the acute inflammatory response. Furthermore, SREBP2 activation was dependent on NF-kB DNA binding and classical SCAP-SREBP2 processing. We used bacterial cytolysin probes to show that inflammatory stress significantly decreased accessible cholesterol, leading to dysfunctional sterol sensing and downstream SREBP2 cleavage. We also explored what role SREBP2 plays in the EC inflammatory response. Loss of SREBP2 in ECs treated with inflammatory cytokine altered EC phenotype, which was defined by decreased chemokine expression and increased type I inflammatory signaling. Interestingly, this effect on the EC inflammatory transcriptome could not be accounted by changes in cholesterol, but rather through SREBP2 binding to promoters of pro-inflammatory transcription factors. Preliminary results revealed that BHLHE40 and KLF6 are direct targets of SREBP2 and that loss of one of KLF6 could mimic the effect of SREBP2 knockdown on chemokine expression. This study is the first to provide an in-depth characterization of the relationship between SREBP2 and the endothelial acute inflammatory response.
2022-07-14 | GSE207919 | GEO
Project description:SREBP2 regulates several genes in the endothelial response to inflammation via direct transcriptional activation of KLF6
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Project description:Sterol regulatory element-binding protein 2 (SREBP2) is a transcription factor that has been recently discovered to mediate vascular endothelial cell (EC) dysfunction. We therefore investigated the role of SREBP2 in EC function through comparing the transciptional profiling of human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus overexpressing SREBP2 (Ad-SREBP2) or with empty vector (Ad-null) control. Gene ontology analysis revealed that SREBP2 not only regulates cholesterol biosynthesis, but also mediates the TGF, WNT, and cytoskeleton remodeling pathways. Among the responsive genes, SREBP2 exhibited the induction of mesenchymal transition.
2019-10-01 | GSE121782 | GEO
Project description:The transcription factor SREBP2 is the main regulator of cholesterol homeostasis and is central to the mechanism of action of lipid-lowering drugs, such as statins, which are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic disease. Recently, SREBP2 has been implicated in leukocyte innate and adaptive immune responses by upregulation of cholesterol flux or direct transcriptional activation of pro-inflammatory genes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and crucial to the pathogenesis of cardiovascular disease. Loss of SREBF2 inhibits the production of pro-inflammatory chemokines but amplifies type I interferon response genes in response to inflammatory stimulus. Furthermore, SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing of endogenous SREBP2 reveals that SREBP2 bound to the promoter regions of two nonclassical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. SREBP2 upregulation of KLF6 was responsible for the downstream amplification of chemokine expression, highlighting a novel relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.
| S-EPMC10407908 | biostudies-literature
Project description:Sterol regulatory element-binding protein 2 (SREBP2) is a transcription factor that has been recently discovered to mediate vascular endothelial cell (EC) dysfunction. We therefore investigated the role of SREBP2 in the epigenetic function of EC biology through comparing ATAC-seq of human umbilical vein endothelial cells (HUVECs) that were infected with adenovirus overexpressing SREBP2 (Ad-SREBP2) or with empty vector (Ad-null) control. Gene ontology analysis revealed that SREBP2 not only decondenses chromatin for cholesterol biosynthesis, but also mediates the TGF pathway. Among the responsive promoter, SREBP2 exhibited the induction of genes related to mesenchymal transition.
2019-10-01 | GSE121781 | GEO
Project description:Metabolic reprogramming is well-appreciated to be able to control macrophage activation. However, it remains unknown whether the SREBPs-lipogenesis pathway is involved in macrophage alternative (or M2) activation. Here, we showed that IL4-induced M2 activation was coupled with increased SREBP2 maturation and activated cholesterol biosynthetic pathway, while the SREBP1-fatty acid biosynthesis pathway remained unaffected after IL4 stimulation. Genetic or pharmacologic blockade of SREBP2 maturation significantly inhibited IL4-induced M2 activation independent of cholesterol. Instead, cholesterol inhibited M2 activation most likely through its feedback regulation of SREBP2 maturation. Mechanically, the upregulation of SREBP2 maturation was dependent on the activation of upstream MTOR, and mature SREBP2 increased the expression of KAZALD1 and subsequently activated the IGF1 signaling to promote IL4-induced M2 activation. Consistently, myeloid-specific Scap deficiency markedly decreased the number of M2 macrophages in the lung and attenuated the HDM-induced allergic airway inflammation. Taken together, these findings highlight a critical role for cholesterol homeostatic regulator SREBP2 in M2 activation, which advances our understanding of the regulation of immunometabolism for M2 activation and points to new opportunities for therapeutic control of M2 activation and allergic airway inflammation.
2023-04-30 | GSE188356 | GEO
Project description:We examine the role of Klf6 in oligodendrocyte progenitor cells and determine that Klf6 acts in part through direct regulation of gp130 signaling and nuclear import via importin-α5 (Impα5), a key controller of nuclear trafficking. Examination of Klf6 DNA binding in two different stages of differentiation
2016-04-01 | E-GEOD-79243 | biostudies-arrayexpress
Project description:We examine the role of Klf6 in oligodendrocyte progenitor cells and determine that Klf6 acts in part through direct regulation of gp130 signaling and nuclear import via importin-α5 (Impα5), a key controller of nuclear trafficking.
2016-04-01 | GSE79243 | GEO
Project description:SREBP2(N) Overexpression in Human Umbilical Vein Endothelial Cells
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