PUBLICATION

AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate

Authors
Gu, Q., Yang, X., Lv, J., Zhang, J., Xia, B., Kim, J.D., Wang, R., Xiong, F., Meng, S., Clements, T.P., Tandon, B., Wagner, D.S., Diaz, M.F., Wenzel, P.L., Miller, Y.I., Traver, D., Cooke, J.P., Li, W., Zon, L.I., Chen, K., Bai, Y., Fang, L.
ID
ZDB-PUB-190917-4
Date
2019
Source
Science (New York, N.Y.)   363: 1085-1088 (Journal)
Registered Authors
Fang, Longhou, Gu, Qilin, Kim, Jun-Dae, Miller, Yury, Traver, David, Wagner, Daniel, Yang, Xiaojie, Zon, Leonard I.
Keywords
none
MeSH Terms
  • Animals
  • Anticholesteremic Agents/pharmacology
  • Atorvastatin/pharmacology
  • Base Sequence
  • Cholesterol/biosynthesis*
  • Chromatin Immunoprecipitation
  • Coronary Artery Disease/metabolism
  • Gene Expression Regulation
  • Hematopoiesis*/genetics
  • Hematopoietic Stem Cells/metabolism*
  • Hypercholesterolemia/metabolism*
  • Receptors, Notch/genetics
  • Sterol Regulatory Element Binding Protein 2/metabolism
  • Zebrafish
PubMed
30705153 Full text @ Science
Abstract
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes