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

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 an...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Yanyan Ding, Yuzhe Li, Ziqian Zhao, Qiangfeng Cliff Zhang, Feng Liu
Formato:	article
Lenguaje:	EN
Publicado:	eLife Sciences Publications Ltd 2021
Materias:	Smarca5 erythrocyte venous thrombosis blood clot Medicine R Science Q Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d6dc594803b7444ca0958207a9ef0e03
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:d6dc594803b7444ca0958207a9ef0e03
record_format	dspace
spelling	oai:doaj.org-article:d6dc594803b7444ca0958207a9ef0e032021-11-16T17:37:16ZThe chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling10.7554/eLife.725572050-084Xe72557https://doaj.org/article/d6dc594803b7444ca0958207a9ef0e032021-10-01T00:00:00Zhttps://elifesciences.org/articles/72557https://doaj.org/toc/2050-084XAlthough 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.Yanyan DingYuzhe LiZiqian ZhaoQiangfeng Cliff ZhangFeng LiueLife Sciences Publications LtdarticleSmarca5erythrocytevenous thrombosisblood clotMedicineRScienceQBiology (General)QH301-705.5ENeLife, Vol 10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Smarca5 erythrocyte venous thrombosis blood clot Medicine R Science Q Biology (General) QH301-705.5
spellingShingle	Smarca5 erythrocyte venous thrombosis blood clot Medicine R Science Q Biology (General) QH301-705.5 Yanyan Ding Yuzhe Li Ziqian Zhao Qiangfeng Cliff Zhang Feng Liu The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
description	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.
format	article
author	Yanyan Ding Yuzhe Li Ziqian Zhao Qiangfeng Cliff Zhang Feng Liu
author_facet	Yanyan Ding Yuzhe Li Ziqian Zhao Qiangfeng Cliff Zhang Feng Liu
author_sort	Yanyan Ding
title	The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
title_short	The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
title_full	The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
title_fullStr	The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
title_full_unstemmed	The chromatin-remodeling enzyme Smarca5 regulates erythrocyte aggregation via Keap1-Nrf2 signaling
title_sort	chromatin-remodeling enzyme smarca5 regulates erythrocyte aggregation via keap1-nrf2 signaling
publisher	eLife Sciences Publications Ltd
publishDate	2021
url	https://doaj.org/article/d6dc594803b7444ca0958207a9ef0e03
work_keys_str_mv	AT yanyanding thechromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT yuzheli thechromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT ziqianzhao thechromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT qiangfengcliffzhang thechromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT fengliu thechromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT yanyanding chromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT yuzheli chromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT ziqianzhao chromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT qiangfengcliffzhang chromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling AT fengliu chromatinremodelingenzymesmarca5regulateserythrocyteaggregationviakeap1nrf2signaling
_version_	1718426328999395328

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

Ejemplares similares