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Potential Roles of Mediator Complex Subunit 13 in Cardiac Diseases

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Potential Roles of Mediator Complex Subunit 13 in Cardiac Diseases Int. J. Biol. Sci. 2021, Vol. 17 328 Ivyspring International Publisher International Journal of Biological Sciences 2021; 17(1): 328-338. doi: 10.7150/ijbs.52290 Review Potential roles of mediator Complex Subunit 13 in Cardiac Diseases Wenqian Zhou1,2, He Cai1, Jia Li2,3, He Xu4, Xiang Wang1,2, Hongbo Men1,2, Yang Zheng1 and Lu Cai2,5 1. The Center of Cardiovascular Diseases, the First Hospital of Jilin University, Changchun 130021, China. 2. Pediatric Research Institute, the Department of Pediatrics of University of Louisville, Louisville, KY 40202, USA. 3. Department of Nephrology, the First Hospital of Jilin University, Changchun 130021, China. 4. Department of Respiratory Medicine, the First Hospital of Jilin University (Eastern Division), Changchun 130031, China. 5. Department of Pharmacology and Toxicology, the University of Louisville, Louisville, KY 40202, USA. Corresponding authors: Yang Zheng, The Center of Cardiovascular Diseases, the First Hospital of Jilin University, 71 Xinmin Street, Changchun, 130021, China. E-mail: [email protected]; Phone: +86-13756661288; Lu Cai, Pediatric Research Institute, 570 South Preston Street, Rm: 304F, Louisville, KY, 40202, USA. E-mail: [email protected]; Phone: 502-852-2214. © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions. Received: 2020.08.22; Accepted: 2020.11.25; Published: 2021.01.01 Abstract Mediator complex subunit 13 (MED13, previously known as THRAP1 and TRAP240) is a subunit of the cyclin-dependent kinase 8 (CDK8) kinase module in the eukaryotic mediator complex. MED13 has been known to play critical roles in cell cycle, development, and growth. The purpose of this review is to comprehensively discuss its newly identified potential roles in myocardial energy metabolism and non-metabolic cardiovascular diseases. Evidence indicates that cardiac MED13 mainly participates in the regulation of nuclear receptor signaling, which drives the transcription of genes involved in modulating cardiac and systemic energy homeostasis. MED13 is also associated with several pathological conditions, such as metabolic syndrome and thyroid disease-associated heart failure. Therefore, MED13 constitutes a potential therapeutic target for the regulation of metabolic disorders and other cardiovascular diseases. Key words: MED13; cardiovascular diseases; energy metabolism Introduction Aberrant gene transcription causes serious target. human diseases [1]. The mediator complex (MED) acts as a structural and functional bridge between MED and MED13 structure and function DNA-binding transcription factors (TFs) and the basal Eukaryotic transcription requires RNA poly- transcriptional machinery [2]. It helps regulate the merase II and various transcriptional repressors and expression of RNA polymerase II-transcribed genes, activators, including TFs, that bind to specific DNA as well as transcription initiation and elongation [3]. sequences in gene enhancer regions. TFs function is Mediator subunit 13 (MED13, known as THRAP1 and regulated by transcriptional co-regulators [5]. The TRAP240) is part of the MED [4]. MED13 maintains MED acts as a co-regulator and contains multiple the transcription of some essential proteins involved subunits (approximately 25 and 30 subunits in yeast in growth and development, and MED13 gene and humans, respectively). It functions as an adaptor mutations are associated with various diseases, between TFs bound to upstream regulatory elements including cardiac diseases. MED13 plays critical roles and the transcription machinery, which includes RNA in diseases like metabolic syndrome and polymerase II and general TFs (GTFs), such as cardiovascular disease. This review will cover the transcription initiation factor II (TFII) A, TFIIB, TFIID, basic structure and functions of MED13 and its TFIIE, TFIIF, and TFIIH [5-7]. The MED is recruited by potential roles in metabolic and non-metabolic cardiac TFs to regulatory regions and binds to RNA diseases. Understanding MED13 biology is critical for polymerase II and GTFs that have been recruited to its optimal manipulation as a potential therapeutic the core promoter to drive formation of the http://www.ijbs.com Int. J. Biol. Sci. 2021, Vol. 17 329 preinitiation complex. The MED mainly transmits conserved, and the protein regulates gene expression signals from TFs to RNA polymerase II (Figure 1) and in numerous physiological growth and regulates the transcription of specific genes, such as developmental processes [12, 17-21] (Table 1). those for nuclear receptors (NRs) [8, 9]. Moreover, MED13 is critical in myogenesis, zygotic Electron microscopy data indicate that the MED genome activation, prevention of mitochondrial is composed of four modules: the head, middle, tail, fission, and programmed cell death [12, 21, 22]. In and cyclin-dependent kinase 8 (CDK8) kinase module mice, MED13/MED13L has an essential function in (CKM) [5, 10]. The CKM comprises CDK8, cyclin C embryonic development. Snijders Blok et al. [23] (Cyc C/CCNC), MED13, and MED12 [11] (Figure 1). reported three missense mutations (p.Pro327Ser, Three CKM proteins, CDK8, MED13, and MED12, p.Thr326Ile, and p.Pro327Gln) and one in-frame have paralogs that can replace them in the kinase deletion (p.Thr326del) in a conserved phosphodegron domain, although they do not perform exactly the of human MED13. Normally, this phosphodegron is same functions [12]: cyclin-dependent kinase 19, recognized by the S-phase kinase-associated protein mediator subunit 13 like protein (MED13L, originally (Skp)-Cullin-F-box (SCF) F-box and WD repeat called PROSIT240 or THRAP2), and mediator subunit domain-containing 7 (Fbw7) ubiquitin ligase complex 12 like protein (MED12L). MED13L is similar in size to (SCFFbw7), resulting in MED13 protein ubiquitination MED13, with which it shares 50% identity at the and degradation [24], suggesting that these mutations protein level [13]. CKM can regulate transcription by may affect MED13 protein turnover. Some MED13 blocking the MED–RNA polymerase II association, gene mutations are reportedly associated with thereby preventing transcription initiation or re- abnormal heart development [25, 26], neuro- initiation [14]. The MED undergoes a conformational developmental disorders, nervous system disorders, change and forms a dynamic bridge between craniofacial dysmorphisms, and muscle diseases [23, enhancers and promoters via reversible dissociation 27, 28] (Table 1). MED13L gene mutations are also of CKM from the MED [11, 15] (Figure 1). associated with these phenotypes, but with more MED13 plays a connective role between the variable features [13, 26, 29-36]. MED13 not only plays CKM and the MED core [16]; therefore, targeting a critical role in necessary physiological processes, MED13 may affect MED transcriptional co-regulatory including organismal growth and development, but is function. In yeast, Caenorhabditis elegans, zebrafish, also involved in pathophysiological processes and Drosophila, and mouse, the MED13 sequence is diseases. Figure 1. The main structure and function of the mediator complex (MED). The MED is composed of four parts: the head, middle, tail, and CKM. The CKM includes CDK8/19, Cyc C/CCNC, MED12/12L, and MED13/13L. (A) The CKM associates with the MED via interaction between MED13 and a “hook” at the end of the MED (middle module). Targeted degradation of MED13 can affect the association between the CKM and the MED. (B) An activator (Act) recruits the MED to an enhancer and then recruits GTFs. (C) The MED helps to recruit RNA polymerase (Pol) II to the promoter via interaction with the non-phosphorylated carboxy-terminal domain (CTD) of RNA polymerase II. MED also helps recruit other factors to promote the formation of the preinitiation complex. (D) This process includes CKM dissociation from the MED. (E) Then, the CTD of RNA polymerase II is phosphorylated (P-CTD) by the GTF TFIIH, which is accompanied by MED dissociation, thereby allowing RNA polymerase II to escape from the promoter and initiate transcription. The MED also regulates RNA polymerase II pausing and elongation. (CKM, cyclin-dependent kinase 8 (CDK8) kinase module; GTF, general transcription factor). http://www.ijbs.com Int. J. Biol. Sci. 2021, Vol. 17 330 Table 1. Comparison of the biological roles and associated phenotypes of MED13 and MED13L MED13 MED13L References Human chromosome 17q23.2 12q24.21 [37] Biological role Growth and development/Myogenesis Neural crest induction/Neurogenesis [19-21, 38-40] Zygotic genome activation/Mitosis/Mitochondrial Cell proliferation [12, 17, 18, 22, 41] fission/PCD Pathophysiological role Target of miR-208a and miR-378/378* — [42, 43] Cyanotic congenital heart disease (A-to-I RNA editing) Congenital heart defect (TGA)/Coarctation of the [13, 25, 33] aorta Neurodevelopmental disorder (DD/ID) MED13L haploinsufficiency syndrome [23, 26, 29-32, 34, 40] ASD/ADHD (broaden the clinical features) PCD: Programmed cell death; DD: Developmental delay; ID: Intellectual disability; A-to-I RNA editing: adenosine-to-inosine RNA editing; ASD: Autism spectrum disorder; ADHD: Attention deficit hyperactivity disorder; TGA: Transposition of the great arteries. highest MED13 expression found in the placenta, MED13 degradation under oxidative skeletal muscle, heart, pancreas, and brain [49]. stress MED13/MED13L plays an important role in Elevated levels of reactive
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