PUBLICATION
Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells
- Authors
- Pessoa Rodrigues, C., Collins, J.M., Yang, S., Martinez, C., Kim, J.W., Lama, C., Nam, A.S., Alt, C., Lin, C., Zon, L.I.
- ID
- ZDB-PUB-240913-2
- Date
- 2024
- Source
- Science (New York, N.Y.) 385: eadn1629eadn1629 (Journal)
- Registered Authors
- Zon, Leonard I.
- Keywords
- none
- MeSH Terms
-
- Phagocytosis*
- Macrophages*/metabolism
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Repetitive Sequences, Nucleic Acid
- PubMed
- 39264994 Full text @ Science
Abstract
Macrophages maintain hematopoietic stem cell (HSC) quality by assessing cell surface Calreticulin (Calr), an "eat-me" signal induced by reactive oxygen species (ROS). Using zebrafish genetics, we identified Beta-2-microglobulin (B2m) as a crucial "don't eat-me" signal on blood stem cells. A chemical screen revealed inducers of surface Calr that promoted HSC proliferation without triggering ROS or macrophage clearance. Whole-genome CRISPR-Cas9 screening showed that Toll-like receptor 3 (Tlr3) signaling regulated b2m expression. Targeting b2m or tlr3 reduced the HSC clonality. Elevated B2m levels correlated with high expression of repetitive element (RE) transcripts. Overall, our data suggest that RE-associated double-stranded RNA could interact with TLR3 to stimulate surface expression of B2m on hematopoietic stem and progenitor cells. These findings suggest that the balance of Calr and B2m regulates macrophage-HSC interactions and defines hematopoietic clonality.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping