The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells

Zilong Li; Baoyu Chen; Xinyu Weng; Liming Yu; Mingzi Song; Mingming Fang; Junli Guo; Yong Xu

doi:10.1016/j.bbagrm.2018.06.004

The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells

Zilong Li, Baoyu Chen, Xinyu Weng, Liming Yu, Mingzi Song, Mingming Fang, Junli Guo, Yong Xu

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Abstract

Thrombomodulin (TM, encoded by the THBD gene) expressed in vascular endothelial cells plays pivotal roles maintaining the equilibrium of coagulation and anti-coagulation. TM levels can be regulated at the transcriptional level although the epigenetic mechanism is underexplored. Here we report that transcriptional activation of TM in both immortalized vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAEC) by all-trans retinoic acid (RA) paralleled accumulation of trimethylated histone H3K4, a prominent marker for active chromatin, surrounding the THBD promoter. RA treatment up-regulated the expression of SETD1A (SET1), a dedicated H3K4 methyltransferase, and augmented SETD1A occupancies on the THBD promoter. Further analysis revealed that the sequence-specific transcription factor Kruppel-like factor 4 (KLF4) interacted with and recruited SETD1A to the THBD promoter. Interestingly, SETD1A was recruited to the KLF4 promoter by retinoic acid receptor (RAR) and mediated the up-regulation of KLF4 expression by RA stimulation. In summary, our data illustrate a previously unrecognized pathway in which SETD1A contributes to RA-induced TM expression in vascular endothelial cells by modulating the activity and expression of KLF4.

Original language	English (US)
Pages (from-to)	752-761
Number of pages	10
Journal	Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume	1861
Issue number	8
DOIs	https://doi.org/10.1016/j.bbagrm.2018.06.004
State	Published - Aug 2018
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported, in part, by grants from the Natural Science Foundation of China ( 81725001 , 81460042 , 81770487 ), Haihan Province R&D Fund Key Project ( ZDYF2018102 ), and Jiangsu Province Higher Education Natural Science Foundation ( 17KJB310002 ).

Funding Information:
This work was supported, in part, by grants from the Natural Science Foundation of China (81725001, 81460042, 81770487), Haihan Province R&D Fund Key Project (ZDYF2018102), and Jiangsu Province Higher Education Natural Science Foundation (17KJB310002).

Publisher Copyright:
© 2018 Elsevier B.V.

Keywords

Endothelial cells
Epigenetics
Thrombomodulin
Transcriptional regulation

PubMed: MeSH publication types

Journal Article
Research Support, Non-U.S. Gov't

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@article{20a0079348f5449692d01385da6eb170,

title = "The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells",

abstract = "Thrombomodulin (TM, encoded by the THBD gene) expressed in vascular endothelial cells plays pivotal roles maintaining the equilibrium of coagulation and anti-coagulation. TM levels can be regulated at the transcriptional level although the epigenetic mechanism is underexplored. Here we report that transcriptional activation of TM in both immortalized vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAEC) by all-trans retinoic acid (RA) paralleled accumulation of trimethylated histone H3K4, a prominent marker for active chromatin, surrounding the THBD promoter. RA treatment up-regulated the expression of SETD1A (SET1), a dedicated H3K4 methyltransferase, and augmented SETD1A occupancies on the THBD promoter. Further analysis revealed that the sequence-specific transcription factor Kruppel-like factor 4 (KLF4) interacted with and recruited SETD1A to the THBD promoter. Interestingly, SETD1A was recruited to the KLF4 promoter by retinoic acid receptor (RAR) and mediated the up-regulation of KLF4 expression by RA stimulation. In summary, our data illustrate a previously unrecognized pathway in which SETD1A contributes to RA-induced TM expression in vascular endothelial cells by modulating the activity and expression of KLF4.",

keywords = "Endothelial cells, Epigenetics, Thrombomodulin, Transcriptional regulation",

author = "Zilong Li and Baoyu Chen and Xinyu Weng and Liming Yu and Mingzi Song and Mingming Fang and Junli Guo and Yong Xu",

note = "Funding Information: This work was supported, in part, by grants from the Natural Science Foundation of China ( 81725001 , 81460042 , 81770487 ), Haihan Province R&D Fund Key Project ( ZDYF2018102 ), and Jiangsu Province Higher Education Natural Science Foundation ( 17KJB310002 ). Funding Information: This work was supported, in part, by grants from the Natural Science Foundation of China (81725001, 81460042, 81770487), Haihan Province R&D Fund Key Project (ZDYF2018102), and Jiangsu Province Higher Education Natural Science Foundation (17KJB310002). Publisher Copyright: {\textcopyright} 2018 Elsevier B.V.",

year = "2018",

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doi = "10.1016/j.bbagrm.2018.06.004",

language = "English (US)",

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AU - Li, Zilong

AU - Chen, Baoyu

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AU - Yu, Liming

AU - Song, Mingzi

AU - Fang, Mingming

AU - Guo, Junli

AU - Xu, Yong

N1 - Funding Information: This work was supported, in part, by grants from the Natural Science Foundation of China ( 81725001 , 81460042 , 81770487 ), Haihan Province R&D Fund Key Project ( ZDYF2018102 ), and Jiangsu Province Higher Education Natural Science Foundation ( 17KJB310002 ). Funding Information: This work was supported, in part, by grants from the Natural Science Foundation of China (81725001, 81460042, 81770487), Haihan Province R&D Fund Key Project (ZDYF2018102), and Jiangsu Province Higher Education Natural Science Foundation (17KJB310002). Publisher Copyright: © 2018 Elsevier B.V.

PY - 2018/8

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N2 - Thrombomodulin (TM, encoded by the THBD gene) expressed in vascular endothelial cells plays pivotal roles maintaining the equilibrium of coagulation and anti-coagulation. TM levels can be regulated at the transcriptional level although the epigenetic mechanism is underexplored. Here we report that transcriptional activation of TM in both immortalized vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAEC) by all-trans retinoic acid (RA) paralleled accumulation of trimethylated histone H3K4, a prominent marker for active chromatin, surrounding the THBD promoter. RA treatment up-regulated the expression of SETD1A (SET1), a dedicated H3K4 methyltransferase, and augmented SETD1A occupancies on the THBD promoter. Further analysis revealed that the sequence-specific transcription factor Kruppel-like factor 4 (KLF4) interacted with and recruited SETD1A to the THBD promoter. Interestingly, SETD1A was recruited to the KLF4 promoter by retinoic acid receptor (RAR) and mediated the up-regulation of KLF4 expression by RA stimulation. In summary, our data illustrate a previously unrecognized pathway in which SETD1A contributes to RA-induced TM expression in vascular endothelial cells by modulating the activity and expression of KLF4.

AB - Thrombomodulin (TM, encoded by the THBD gene) expressed in vascular endothelial cells plays pivotal roles maintaining the equilibrium of coagulation and anti-coagulation. TM levels can be regulated at the transcriptional level although the epigenetic mechanism is underexplored. Here we report that transcriptional activation of TM in both immortalized vascular endothelial cells (EAhy926) and primary human aortic endothelial cells (HAEC) by all-trans retinoic acid (RA) paralleled accumulation of trimethylated histone H3K4, a prominent marker for active chromatin, surrounding the THBD promoter. RA treatment up-regulated the expression of SETD1A (SET1), a dedicated H3K4 methyltransferase, and augmented SETD1A occupancies on the THBD promoter. Further analysis revealed that the sequence-specific transcription factor Kruppel-like factor 4 (KLF4) interacted with and recruited SETD1A to the THBD promoter. Interestingly, SETD1A was recruited to the KLF4 promoter by retinoic acid receptor (RAR) and mediated the up-regulation of KLF4 expression by RA stimulation. In summary, our data illustrate a previously unrecognized pathway in which SETD1A contributes to RA-induced TM expression in vascular endothelial cells by modulating the activity and expression of KLF4.

KW - Endothelial cells

KW - Epigenetics

KW - Thrombomodulin

KW - Transcriptional regulation

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The histone methyltransferase SETD1A regulates thrombomodulin transcription in vascular endothelial cells

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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