The Max-Planck Center for Tissue Stem Cell Research and Regenerative Medicine, Bioland Laboratory, Guangzhou, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Yuzhe Li
MOE Key Laboratory of Bioinformatics, Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
Ziqian Zhao
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Qiangfeng Cliff Zhang
MOE Key Laboratory of Bioinformatics, Beijing Advanced Innovation Center for Structural Biology & Frontier Research Center for Biological Structure, Center for Synthetic and Systems Biology, School of Life Sciences, Tsinghua University, Beijing, China; Tsinghua-Peking Center for Life Sciences, Beijing, China
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
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.
