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.

Identification of m6A modification patterns and development of m6A–hypoxia prognostic signature to characterize tumor microenvironment in triple-negative breast cancer

“…SMARCA5 is a chromatin-remodeling enzyme which has been reported related to Keap1-Nrf2 signaling. But its role in cancer is still undiscovered, which needs further exploration ( 54 ). ABCB10(ABC Transporter 10 Protein) is a member of the MDR/TAP subfamily, which are involved in multidrug resistance but the function of ABCB10 require further identification ( 55 ).…”

Protocol for isolation and ATAC-seq library construction of zebrafish red blood cells

“…The circulating erythrocytes which are labelled by gata1 :dsRed can be sorted based on the fluorescent protein expression. 1 Collect the Tg ( gata1 :dsRed) zebrafish embryos into the 60 mm culture dish. Add 1 mL DPBS into dish using a pipette.…”

Hyperglycemia-Suppressed SMARCA5 Disrupts Transcriptional Homeostasis to Facilitate Endothelial Dysfunction in Diabetes

“…Likewise, deregulated SMARCA5 expression has been functionally linked to leukemia [ 8 ], glioblastoma [ 9 ] and breast [ 10 ], lung [ 11 ], and gastric cancers [ 12 ]. Nonetheless, information about the potential contribution SMARCA5 in the regulation of the non-malignant actions remains surprisingly limited, despite recent biochemical evidence in a genetically engineered Zebrafish model suggesting that SMARCA5 signaling may regulate erythrocyte aggregation or development of hematopoietic stem and progenitor cells (HSPCs) via its epigenetic programming ability [ 13 , 14 ]. In the present study, we aimed to characterize more deeply the expression pattern and possible roles of SMARCA5 in the potential regulation of EC function.…”