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
-
- beta 2-Microglobulin*/genetics
- beta 2-Microglobulin*/metabolism
- Cell Proliferation
- Repetitive Sequences, Nucleic Acid
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism
- Signal Transduction
- Macrophages*/metabolism
- Calreticulin*/genetics
- Calreticulin*/metabolism
- Animals
- Hematopoietic Stem Cells*/cytology
- Hematopoietic Stem Cells*/metabolism
- CRISPR-Cas Systems
- Reactive Oxygen Species/metabolism
- Phagocytosis*
- Toll-Like Receptor 3*/genetics
- Toll-Like Receptor 3*/metabolism
- Zebrafish
- PubMed
- 39264994 Full text @ Science
Citation
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. (2024) Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells. Science (New York, N.Y.). 385:eadn1629eadn1629.
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