AIBP-mediated Cholesterol Efflux Instructs Hematopoietic Stem and Progenitor Cell Fate
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ABSTRACT:
PROVIDER: PRJNA503977 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8163631.fastq.gz | Fastqsanger.gz | |||
| SRR8163632.fastq.gz | Fastqsanger.gz |
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Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are underexplored. Here we report that a novel somite-derived pro-hematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch upregulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide ChIP-seq, RNA-seq, and ATAC-seq indicate that Srebp2 trans-regulates Notch pathway genes required for hematopoiesis. Our studies outline a novel AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
2019-05-23 | GSE122204 | GEO
Project description:Hypercholesterolemia, the driving force of atherosclerosis, accelerates the expansion and mobilization of hematopoietic stem and progenitor cells (HSPCs). The molecular determinants connecting hypercholesterolemia with hematopoiesis are unclear. Here, we report that a somite-derived prohematopoietic cue, AIBP, orchestrates HSPC emergence from the hemogenic endothelium, a type of specialized endothelium manifesting hematopoietic potential. Mechanistically, AIBP-mediated cholesterol efflux activates endothelial Srebp2, the master transcription factor for cholesterol biosynthesis, which in turn transactivates Notch and promotes HSPC emergence. Srebp2 inhibition impairs hypercholesterolemia-induced HSPC expansion. Srebp2 activation and Notch up-regulation are associated with HSPC expansion in hypercholesterolemic human subjects. Genome-wide chromatin immunoprecipitation followed by sequencing (ChIP-seq), RNA sequencing (RNA-seq), and assay for transposase-accessible chromatin using sequencing (ATAC-seq) indicate that Srebp2 transregulates Notch pathway genes required for hematopoiesis. Our studies outline an AIBP-regulated Srebp2-dependent paradigm for HSPC emergence in development and HPSC expansion in atherosclerotic cardiovascular disease.
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Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.
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Project description:The activation of Liver X Receptor (LXR) promotes cholesterol efflux and repression of inflammatory genes with anti-atherogenic consequences. The mechanisms underlying repressive activity of LXR are controversial and have been attributed to cholesterol efflux or to transrepression of Activator Protein-1 (AP-1) activity. Here, we find that cholesterol efflux contributes to LXR repression, while direct repressive functions of LXR also play a key role but are independent of AP-1. We use ATAC-seq to show that LXR reduces chromatin accessibility in cis at inflammatory gene enhancers containing LXR binding sites. Targets of this repressive activity are associated with leukocyte adhesion and neutrophil migration, and LXR agonist treatment suppresses neutrophil recruitment in a mouse model of sterile peritonitis. These studies suggest a model of repression in which liganded LXR binds in cis to canonical nuclear receptor binding sites and represses pro-atherogenic leukocyte functions in tandem with induction of LXR targets mediating cholesterol efflux.
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