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Histone Methylation and Vascular Biology Xiang Wei1,2,3,4†, Xin Yi5†, Xue-Hai Zhu1,2,3,4 and Ding-Sheng Jiang1,2,3,4*

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Histone Methylation and Vascular Biology Xiang Wei1,2,3,4†, Xin Yi5†, Xue-Hai Zhu1,2,3,4 and Ding-Sheng Jiang1,2,3,4* Wei et al. Clinical Epigenetics (2020) 12:30 https://doi.org/10.1186/s13148-020-00826-4 REVIEW Open Access Histone methylation and vascular biology Xiang Wei1,2,3,4†, Xin Yi5†, Xue-Hai Zhu1,2,3,4 and Ding-Sheng Jiang1,2,3,4* Abstract The vasculature not only transports oxygenated blood, metabolites, and waste products but also serves as a conduit for hormonal communication between distant tissues. Therefore, it is important to maintain homeostasis within the vasculature. Recent studies have greatly expanded our understanding of the regulation of vasculature development and vascular-related diseases at the epigenetic level, including by protein posttranslational modifications, DNA methylation, and noncoding RNAs. Integrating epigenetic mechanisms into the pathophysiologic conceptualization of complex and multifactorial vascular-related diseases may provide promising therapeutic approaches. Several reviews have presented detailed discussions of epigenetic mechanisms not including histone methylation in vascular biology. In this review, we primarily discuss histone methylation in vascular development and maturity, and in vascular diseases. Keywords: Histone methylation, Histone methyltransferase, Demethylase, Atherosclerosis, Intimal hyperplasia, Aortic dissection/aneurysm, Pulmonary arterial hypertension, Diabetic angiopathy, Cancer angiogenesis The vasculature, which consists of arterial, venous, and pulmonary arterial hypertension [7], diabetic angiopathy interconnecting capillary beds, is formed through vasculo- [8], or arteritis [9]. Multiple mechanisms are involved in the genesis or angiogenesis during embryogenesis. The walls of shift from the physiological status to the pathological state the vessels are composed of endothelial cells, mural cells, of the vasculature. Among them, epigenetic mechanisms and the extracellular matrix (ECM). The origin, number, (e.g., posttranslational modification, RNA methylation, type, and organization of mural cells depend on the loca- DNA methylation, and miRNA) play an indispensable role tion of the vessel and its function. For example, the smooth during these processes [10, 11]. Several published reviews muscle cells (SMCs) of the ascending and arch portions of have summarized epigenetic regulation in vascular biology; the aorta originate from the neural crest, while the SMCs in particular, noncoding RNAs, DNA methylation, and pro- of the descending thoracic aorta are contributed by somite- tein acetylation and phosphorylation have been widely dis- derived cells [1]. The vasculature, a highly branched, tree- cussed [12–14]. In recent years, m6A RNA methylation has like, tubular network, not only transports oxygenated blood, emerged as anewresearch field,butthefunctionsofm6A metabolites, and waste products but also serves as a conduit RNA methylation in vascular development and vascular for hormonal communication between distant tissues. Fur- diseases remain to be revealed. In contrast, histone methy- thermore, the vasculature facilitates rapid deployment of lation has been investigated extensively in vascular biology immune responses to distal sites within the body [2]. Main- after the discoveries of the first histone methyltransferase taining vascular biologic homeostasis is essential for the (HMT) in 2000 and the first histone demethylase in 2004 body; once this balance is disrupted, the vasculature will [15, 16]. Therefore, in the present review, we focus only on suffer from dysplasia or diseases, such as angiodysplasia [3], histone methylation and systematically summarize the re- aortic aneurysm/dissection [4], atherosclerosis [5, 6], search on the roles of histone methylation and mechanisms by which it is involved in vascular development and diseases. * Correspondence: [email protected] †Xiang Wei and Xin Yi contributed equally to this work. 1Division of Cardiothoracic and Vascular Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Histone methylation Jiefang Ave, Wuhan 430030, China Histone methylation, a reversible posttranslational modi- 2Key Laboratory of Organ Transplantation, Ministry of Education, Wuhan, Hubei, China fication, is written by HMTs and erased by histone Full list of author information is available at the end of the article demethylases (HDMTs) [17]. To date, two main types of © The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wei et al. Clinical Epigenetics (2020) 12:30 Page 2 of 17 histone methylation have been identified: methylation on found to be methylated by HMTs [28, 29]. Methylation lysine and arginine residues. Correspondingly, HMTs on nonhistone proteins is associated with other post- have been divided into two categories: protein lysine translational modifications (PTMs), such as phosphoryl- methyltransferases (PKMTs) and protein arginine meth- ation and acetylation, which affects the activity or stabil- yltransferases (PRMTs) [18, 19]. The ε-amine group of ity of proteins [30–32]. In recent years, many studies lysine can be marked with monomethylation (me1), have revealed that histone methylation is involved in and dimethylation (me2), and trimethylation (me3) by sup- indispensable for the development of a variety of vascu- pressor of variegation, enhancer of Zeste, Trithorax lar diseases. In this review, we discuss the role of histone (SET) domain-containing PKMTs or non-SET-domain- methylation on vascular development and maturity, ath- containing PKMTs [18, 20, 21] (Fig. 1a). In contrast, ar- erosclerosis and vascular intimal hyperplasia, acute thor- ginine is methylated by PRMTs at ω-amino groups, acic aortic syndromes and aortic aneurysms, pulmonary which appeared as monomethylation (MMA, Rme1), arterial hypertension, diabetic angiopathy, endothelial symmetric dimethylarginine (SDMA, Rme2s), and asym- dysfunction, and other forms of vasculopathy. metric dimethylarginine (ADMA, Rme2a) (Fig. 1b)[22]. S-Adenosyl-L-methionine (AdoMet), the primary methyl Histone methylation in vascular development and group donor, interacts with PKMTs or PRMTs to trans- maturity fer methyl groups to the lysine or arginine residues (Fig. Defects in placental vascular development cause embry- 1)[23]. A variety of substrates can be methylated by onic death and abnormal organogenesis, negatively affect HMTs, with canonical substrates being histones, such as fetal growth, or confer a higher risk of disease during post- H3K27, H3K4, H3K9, H4K20, and H3R17 [24–27]. natal life [33]. Vascular remodeling is an important However, with further research, an increasing number of pregnancy-associated adaptation in hemochorial placenta- nonhistone proteins (e.g., p53, Rb, and Hsp90) have been tion, and the most common cause of placental dysfunction Fig. 1 A schematic diagram of histone methylation on lysine or arginine residues. Protein can be methylated by methyltransferases and S- adenosyl-L-methionine (AdoMet) is used as the primary methylgroup donor, while these modifications are reversible and can be erased by demethylases. a Protein lysine methyltransferases (PKMTs) catalyze monomethylation (Kme1), dimethylation (Kme2) and trimethylation (Kme3) of proteins on the ε-amine group of lysine. b Protein arginine methyltransferases (PRMTs) methylate the ω-amino group of arginine residues, resulting in either monomethylated (Rme1) or symmetric (Rme2s) or asymmetric (Rme2a) dimethylation. PKDMs protein lysine demethylases, PRDMs protein arginine demethylases Wei et al. Clinical Epigenetics (2020) 12:30 Page 3 of 17 is the failure of vascular remodeling by extravillous placentae from intrauterine growth restriction-affected trophoblast [34]. As reported by Rodesch et al. in 1992, pregnancies [33]. Given that the expression of Jagged1, a they found that relatively hypoxic environment within the ligand involved in Notch signaling, was linked to in- intervillous space of placenta (varies between 2 and 8%) creased circulating plasma VEGF in giant cell arteritis than endometrial oxygen tension during early implant- patient blood vessels, VEGF enhanced Jagged1 expres- ation [35, 36]. This environment is thought to facilitate sion and vessel wall inflammation in mice which were the villous capillary network continued sprouting and re- implanted with patient peripheral blood mononuclear modeling throughout gestation [37]. The HIF signaling is cells and human arteries [45]. Furthermore, Spuul et al. a classic oxygen-sensitive pathway to regulate angiogenesis demonstrated that VEGF/Notch signaling regulates the under hypoxic environments. Hypoxia activates Hif- formation of functional podosomes in endothelial cells dependent expression of lysine demethylase 3A (Kdm3a) to promote retinal neovascularization [46]. However, which demethylates H3K9 to accelerate Mmp12 expres- how histone methylation and its corresponding HMTs sion to facilitate trophoblast invasion and uterine vascular or HDMTs cooperates with VEGF/Notch signaling to remodeling [38]. regulate vascular development and maturity need
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