ZFIN ID: ZDB-PUB-190917-4
AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate
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.
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
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.