@article{f2c6cf7a199a4e03bedc2cb2397bec2d,
title = "Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production",
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. Weinreb et al. show a link between R-loops, inflammation, and the developing hematopoietic system. Ddx41 acts as a gatekeeper of HSPC production by suppressing R-loop accumulation and the cGAS-STING inflammatory pathway. Elevated R-loops and inflammatory signaling were also observed in human cells with decreased DDX41, suggesting possible conservation of mechanism.",
keywords = "Ddx41, R-loops, hematopoietic stem and progenitor cell, inflammatory signaling, zebrafish",
author = "Weinreb, {Joshua T.} and Noura Ghazale and Kith Pradhan and Varun Gupta and Potts, {Kathryn S.} and Brad Tricomi and Daniels, {Noah J.} and Padgett, {Richard A.} and {De Oliveira}, Sofia and Amit Verma and Bowman, {Teresa V.}",
note = "Funding Information: This work was funded by American Cancer Society RSG-129527-DDC, Kimmel Foundation, the Edward P. Evans Foundation, DOD BM180109, 1R56DK121738-01, 1R01DK121728-01A1 (to T.V.B.), MSTP training grant T32GM007288-45 and F30 fellowship 1F30HL142161 (to J.T.W.), T32 GM007491 (to N.G.), R01HL139487 and R01HL150832 (to A.V.), the American Australian Association Sir Rupert Murdoch Postdoctoral Fellowship (to K.S.P.), and R01-HL132071 and a grant from the Vera and Joseph Dresner Foundation (to R.A.P.). We want to thank Eirini Trompouki, Charles Query, Andreas Jenny, and Sara Nik for helpful discussions regarding this work. We want to thank Mary Goll for sharing the stingmk30 mutant zebrafish. We also want to acknowledge the assistance of numerous Core Facilities at Albert Einstein College of Medicine including flow cytometry, Analytical Imaging, and Genomics Facilities (funded by NCI Cancer grant P30CA013330), as well as the Zebrafish Core Facility. J.T.W. A.V. and T.V.B. designed the project experimental approach. J.T.W. N.G. K.S.P. B.T. and S.D.O. performed the experiments. K.P. and V.G. performed bioinformatics analysis. N.J.D. and R.A.P. shared critical reagents. J.T.W. and T.V.B. analyzed the data. J.T.W. and T.V.B. wrote the manuscript; all authors reviewed and approved the manuscript. The authors declare no competing interests. Funding Information: We want to thank Eirini Trompouki, Charles Query, Andreas Jenny, and Sara Nik for helpful discussions regarding this work. We want to thank Mary Goll for sharing the sting mk30 mutant zebrafish. We also want to acknowledge the assistance of numerous Core Facilities at Albert Einstein College of Medicine including flow cytometry, Analytical Imaging, and Genomics Facilities (funded by NCI Cancer grant P30CA013330 ), as well as the Zebrafish Core Facility. Funding Information: This work was funded by American Cancer Society RSG-129527-DDC , Kimmel Foundation , the Edward P. Evans Foundation , DOD BM180109 , 1R56DK121738-01 , 1R01DK121728-01A1 (to T.V.B.), MSTP training grant T32GM007288-45 and F30 fellowship 1F30HL142161 (to J.T.W.), T32 GM007491 (to N.G.), R01HL139487 and R01HL150832 (to A.V.), the American Australian Association Sir Rupert Murdoch Postdoctoral Fellowship (to K.S.P.), and R01-HL132071 and a grant from the Vera and Joseph Dresner Foundation (to R.A.P.). Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = mar,
day = "8",
doi = "10.1016/j.devcel.2021.02.006",
language = "English (US)",
volume = "56",
pages = "627--640.e5",
journal = "Developmental cell",
issn = "1534-5807",
publisher = "Cell Press",
number = "5",
}