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
Citation
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. (2019) AIBP-mediated cholesterol efflux instructs hematopoietic stem and progenitor cell fate. Science (New York, N.Y.). 363:1085-1088.
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping