The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling

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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 smarca5^zko1049a embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in smarca5^zko1049a. To explore the regulatory mechanism of smarca5 in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from smarca5^zko1049a 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).

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Yanyan Ding

University of Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Yuzhe Li

Tsinghua University, Beijing,c, China

Competing interests
The authors declare that no competing interests exist.
Zhiqian Zhao

University of Chinese Academy of Sciences, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Qiangfeng Cliff Zhang

Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Feng Liu

University of Chinese Academy of Sciences, Beijing, China

For correspondence
liuf@ioz.ac.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3228-0943

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.

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).

Copyright

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.