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

• 成果类型: Article
• 署名作者: Pessoa Rodrigues, Cecilia; Collins, Joseph M.; Yang, Song; Martinez, Catherine; Kim, Ji Wook; Lama, Chhiring; Nam, Anna S.; Alt, Clemens; Lin, Charles; Zon, Leonard I.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Howard Hughes Medical Institute; Harvard University; Cornell University; Weill Cornell Medicine; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13825
• DOI: 10.1126/science.adn1629
• 发表日期: 2024-09-13
• 页码: 1181-+
• 关键词: mhc class-i; scale crispr-cas9 knockout; gene-expression; azacitidine; zebrafish; rna; calreticulin; macrophages; activation; deficient

摘要

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.