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Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production.

Joshua T Weinreb1, Noura Ghazale1, Kith Pradhan2

  • 1Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, USA; Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

Developmental Cell
|March 2, 2021
PubMed
Summary

DEAD-box helicase 41 (Ddx41) regulates hematopoietic stem and progenitor cell (HSPC) production by preventing R-loop accumulation. Disrupting this balance activates inflammatory pathways, increasing HSPC numbers.

Keywords:
Ddx41R-loopshematopoietic stem and progenitor cellinflammatory signalingzebrafish

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Area of Science:

  • Developmental Biology
  • Hematopoiesis
  • Molecular Biology

Background:

  • Hematopoietic stem and progenitor cells (HSPCs) are crucial for lifelong blood and immune system function.
  • Maintaining proper HSPC numbers is vital for hematopoietic homeostasis.
  • The precise molecular mechanisms controlling HSPC production require further elucidation.

Purpose of the Study:

  • To identify key regulators of hematopoietic stem and progenitor cell (HSPC) production during development.
  • To investigate the role of DEAD-box helicase 41 (Ddx41) in HSPC regulation.
  • To understand the molecular pathways linking Ddx41 function to HSPC homeostasis.

Main Methods:

  • Utilized zebrafish (Danio rerio) as a model organism to study ddx41 mutants.
  • Analyzed the endothelial-to-hematopoietic transition in developing zebrafish embryos.
  • Investigated the impact of R-loop accumulation on cellular signaling pathways, including cGAS-STING.

Main Results:

  • DEAD-box helicase 41 (Ddx41) was identified as a critical regulator of HSPC production.
  • Zebrafish ddx41 mutants exhibited dysregulated HSPC numbers due to excess R-loop accumulation.
  • Excess R-loops in ddx41 mutants activated the cGAS-STING inflammatory pathway, increasing hemogenic endothelium and HSPC populations.
  • Similar R-loop accumulation and inflammatory signaling were observed in human cells with reduced DDX41 expression.

Conclusions:

  • Ddx41 acts as a gatekeeper, suppressing R-loop accumulation to control HSPC production.
  • Aberrant R-loop levels disrupt cellular homeostasis by activating the cGAS-STING pathway.
  • Precise regulation of R-loop dynamics during development is essential for limiting cGAS-STING activity and maintaining appropriate HSPC numbers.