The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
Abstract
Although thrombosis has been extensively studied using various animal models, our understanding of the underlying mechanism remains elusive. Here, using zebrafish model, we demonstrated that smarca5-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat smarca5zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5zko1049a and their siblings and found that both the chromatin accessibility at the keap1a promoter and expression of keap1a were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of hmox1a, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon smarca5 deletion. Importantly, overexpression of keap1a or knockdown of hmox1a partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in smarca5 mutants. Together, our study using zebrafish smarca5 mutants characterizes a novel role for smarca5 in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.
Data availability
The accession number for the sequencing raw data in this paper is BioProject: PRJNA716463. Source data of supplemental Figure 6D was provided, including the original files of the full raw unedited blots (supplemental Figure 6-source data 2 and 4) and figures with the uncropped blots with the relevant bands clearly labelled (supplemental Figure 6-source data 1 and 3).
Article and author information
Author details
Funding
natioinal key research and developmetal program of China (2018YFA0800200)
- Feng Liu
Max Planck Institute for Dynamics of Complex Technical Systems Magdeburg
- Zhiqian Zhao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China
Ethics
Animal experimentation: The present study was approved by the Ethical Review Committee of the Institute of Zoology, Chinese Academy of Sciences, China (IOZ-IACUC-2020-010).
Version history
- Received: July 27, 2021
- Preprint posted: September 9, 2021 (view preprint)
- Accepted: October 23, 2021
- Accepted Manuscript published: October 26, 2021 (version 1)
- Version of Record published: November 16, 2021 (version 2)
Copyright
© 2021, Ding et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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