Transcripts of repetitive DNA elements signal to block phagocytosis of hematopoietic stem cells.

Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 0404511 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-9203 (Electronic) Linking ISSN: 00368075 NLM ISO Abbreviation: Science Subsets: MEDLINE

Publication: : Washington, DC : American Association for the Advancement of Science
Original Publication: New York, N.Y. : [s.n.] 1880-

beta 2-Microglobulin*/genetics ; beta 2-Microglobulin*/metabolism ; Calreticulin*/metabolism ; Calreticulin*/genetics ; Hematopoietic Stem Cells*/metabolism ; Hematopoietic Stem Cells*/cytology ; Macrophages*/metabolism ; Phagocytosis* ; Toll-Like Receptor 3*/metabolism ; Toll-Like Receptor 3*/genetics; Animals ; Cell Proliferation ; CRISPR-Cas Systems ; Reactive Oxygen Species/metabolism ; Repetitive Sequences, Nucleic Acid ; Signal Transduction ; Zebrafish ; Zebrafish Proteins/metabolism ; Zebrafish Proteins/genetics

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.

0 (beta 2-Microglobulin)
0 (Calreticulin)
0 (Reactive Oxygen Species)
0 (Toll-Like Receptor 3)
0 (Zebrafish Proteins)

Date Created: 20240912 Date Completed: 20240912 Latest Revision: 20240912

20240913

10.1126/science.adn1629

39264994