PUBLICATION
Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production
- Authors
- Weinreb, J.T., Ghazale, N., Pradhan, K., Gupta, V., Potts, K.S., Tricomi, B., Daniels, N.J., Padgett, R.A., De Oliveira, S., Verma, A., Bowman, T.V.
- ID
- ZDB-PUB-210303-11
- Date
- 2021
- Source
- Developmental Cell 56(5): 627-640.e5 (Journal)
- Registered Authors
- Bowman, Teresa, de Oliveira, Sofia
- Keywords
- Ddx41, R-loops, hematopoietic stem and progenitor cell, inflammatory signaling, zebrafish
- Datasets
- GEO:GSE146995
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Differentiation
- DEAD-box RNA Helicases/genetics
- DEAD-box RNA Helicases/metabolism
- Embryo, Nonmammalian/cytology*
- Embryo, Nonmammalian/metabolism
- Hematopoietic Stem Cells/cytology*
- Hematopoietic Stem Cells/metabolism
- Membrane Proteins/genetics
- Membrane Proteins/metabolism
- Nucleotidyltransferases/genetics
- Nucleotidyltransferases/metabolism
- R-Loop Structures*
- Signal Transduction
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 33651979 Full text @ Dev. Cell
Citation
Weinreb, J.T., Ghazale, N., Pradhan, K., Gupta, V., Potts, K.S., Tricomi, B., Daniels, N.J., Padgett, R.A., De Oliveira, S., Verma, A., Bowman, T.V. (2021) Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production. Developmental Cell. 56(5):627-640.e5.
Abstract
Hematopoietic stem and progenitor cells (HSPCs) arise during embryonic development and are essential for sustaining the blood and immune systems throughout life. Tight regulation of HSPC numbers is critical for hematopoietic homeostasis. Here, we identified DEAD-box helicase 41 (Ddx41) as a gatekeeper of HSPC production. Using zebrafish ddx41 mutants, we unveiled a critical role for this helicase in regulating HSPC production at the endothelial-to-hematopoietic transition. We determined that Ddx41 suppresses the accumulation of R-loops, nucleic acid structures consisting of RNA:DNA hybrids and ssDNAs whose equilibrium is essential for cellular fitness. Excess R-loop levels in ddx41 mutants triggered the cGAS-STING inflammatory pathway leading to increased numbers of hemogenic endothelium and HSPCs. Elevated R-loop accumulation and inflammatory signaling were observed in human cells with decreased DDX41, suggesting possible conservation of mechanism. These findings delineate that precise regulation of R-loop levels during development is critical for limiting cGAS-STING activity and HSPC numbers.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping