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

• Published in: eLife Vol. 10
• Main Authors: Ding, Yanyan, Li, Yuzhe, Zhao, Ziqian, Cliff Zhang, Qiangfeng, Liu, Feng
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 26-10-2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adenosine Triphosphatases - genetics; Adenosine Triphosphatases - metabolism; Analysis; Anemia; Animal models; Animals; Argatroban; Blood clot; Blood clots; Blood coagulation; Blood vessels; Carrier Proteins - genetics; Carrier Proteins - metabolism; Chromatin; Chromatin remodeling; Danio rerio; Developmental Biology; Drug screening; Embryos; Enzymes; Epigenetics; erythrocyte; Erythrocyte Aggregation - genetics; Erythrocytes; Gene expression; Hemoglobin; Homeostasis; Mutants; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Physiological aspects; Siblings; Signal Transduction; Smarca5; Thrombin; Thrombosis; Transcriptomes; Veins & arteries; venous thrombosis; Zebrafish - genetics; Zebrafish - physiology; Zebrafish Proteins - genetics; Zebrafish Proteins - metabolism; zebrafish; blood clot; Smarca5; developmental biology; venous thrombosis; erythrocyte
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.72557

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
-deficient red blood cells (RBCs) formed blood clots in the caudal vein plexus. We further used the anti-thrombosis drugs to treat
embryos and found that a thrombin inhibitor, argatroban, partially prevented blood clot formation in
. To explore the regulatory mechanism of
in RBC homeostasis, we profiled the chromatin accessibility landscape and transcriptome features in RBCs from
and their siblings and found that both the chromatin accessibility at the
promoter and expression of
were decreased. Keap1 is a suppressor protein of Nrf2, which is a major regulator of oxidative responses. We further identified that the expression of
, a downstream target of Keap1-Nrf2 signaling pathway, was markedly increased upon
deletion. Importantly, overexpression of
or knockdown of
partially rescued the blood clot formation, suggesting that the disrupted Keap1-Nrf2 signaling is responsible for the RBC aggregation in
mutants. Together, our study using zebrafish
mutants characterizes a novel role for
in RBC aggregation, which may provide a new venous thrombosis animal model to support drug screening and pre-clinical therapeutic assessments to treat thrombosis.