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
  • Animals
  • Hematopoietic Stem Cells*/cytology
  • Hematopoietic Stem Cells*/metabolism
  • CRISPR-Cas Systems
  • beta 2-Microglobulin*/genetics
  • beta 2-Microglobulin*/metabolism
  • Signal Transduction
  • Toll-Like Receptor 3*/genetics
  • Toll-Like Receptor 3*/metabolism
  • Zebrafish
  • Reactive Oxygen Species/metabolism
  • Calreticulin*/genetics
  • Calreticulin*/metabolism
  • Cell Proliferation
(all 19)
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
Figures
Figure Gallery (4 images)
Show all Figures
Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    Complex
    a131TgTransgenic Insertion
      cz2010TgTransgenic Insertion
        cz3332TgTransgenic Insertion
          cz3333TgTransgenic Insertion
            cz3340TgTransgenic Insertion
              gl22TgTransgenic Insertion
                sa13360
                  Point Mutation
                  w2
                    Point Mutation
                    z207TgTransgenic Insertion
                      1 - 10 of 10
                      Show
                      Human Disease / Model
                      No data available
                      Sequence Targeting Reagents
                      Target Reagent Reagent Type
                      b2mCRISPR2-b2mCRISPR
                      calr3bCRISPR1-calr3bCRISPR
                      irf3CRISPR4-irf3CRISPR
                      irf8MO2-irf8MRPHLNO
                      tlr3CRISPR6-tlr3CRISPR
                      tlr3MO1-tlr3MRPHLNO
                      1 - 6 of 6
                      Show
                      Fish
                      No data available
                      Antibodies
                      No data available
                      Orthology
                      No data available
                      Engineered Foreign Genes
                      Marker Marker Type Name
                      CeruleanEFGCerulean
                      CreEFGCre
                      EGFPEFGEGFP
                      mCherryEFGmCherry
                      TagBFPEFGTagBFP
                      TomatoEFGTomato
                      VenusEFGVenus
                      YFPEFGYFP
                      1 - 8 of 8
                      Show
                      Mapping
                      No data available