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Altered DNA Methylation Pattern Reveal Epigenetic Regulation Of Liu et al. Clin Epigenet (2021) 13:124 https://doi.org/10.1186/s13148-021-01110-9 RESEARCH Open Access Altered DNA methylation pattern reveals epigenetic regulation of Hox genes in thoracic aortic dissection and serves as a biomarker in disease diagnosis Peiru Liu1†, Jing Zhang2,3,4†, Duo Du1, Dandan Zhang1, Zelin Jin1, Wenqing Qiu1, Xiushi Zhou3, Shulong Dong1, Mengyu Zhou1, Heyu Zhao1, Wei Zhang3, Jiakang Ma1, Shaoyang Sun1, Weiguo Fu2,3*, Yun Liu1,5* and Lixin Wang2,3* Abstract Background: Thoracic aortic dissection (TAD) is a severe disease with limited understandings in its pathogenesis. Altered DNA methylation has been revealed to be involved in many diseases etiology. Few studies have examined the role of DNA methylation in the development of TAD. This study explored alterations of the DNA methylation land- scape in TAD and examined the potential role of cell-free DNA (cfDNA) methylation as a biomarker in TAD diagnosis. Results: Ascending aortic tissues from TAD patients (Stanford type A; n 6) and healthy controls (n 6) were frst examined via whole-genome bisulfte sequencing (WGBS). While no obvious= global methylation shift= was observed, numerous diferentially methylated regions (DMRs) were identifed, with associated genes enriched in the areas of vasculature and heart development. We further confrmed the methylation and expression changes in homeobox (Hox) clusters with 10 independent samples using bisulfte pyrosequencing and quantitative real-time PCR (qPCR). Among these, HOXA5, HOXB6 and HOXC6 were signifcantly down-regulated in TAD samples relative to controls. To evaluate cfDNA methylation pattern as a biomarker in TAD diagnosis, cfDNA from TAD patients (Stanford type A; n 7) and healthy controls (n 4) were examined by WGBS. A prediction model was built using DMRs identifed previously= from aortic tissues on methylation= data from cfDNA. Both high sensitivity (86%) and specifcity (75%) were achieved in patient classifcation (AUC 0.96). = Conclusions: These fndings showed an altered epigenetic regulation in TAD patients. This altered epigenetic regula- tion and subsequent altered expression of genes associated with vasculature and heart development, such as Hox family genes, may contribute to the loss of aortic integrity and TAD pathogenesis. Additionally, the cfDNA methylation in TAD was highly disease specifc, which can be used as a non-invasive biomarker for disease prediction. *Correspondence: [email protected]; [email protected]; wang. [email protected] †Peiru Liu and Jin Zhang: contributed equally to this work 2 Vascular Surgery Department, Zhongshan Xiamen Hospital, Fudan University, Xiamen, People’s Republic of China 5 State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, People’s Republic of China Full list of author information is available at the end of the article © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Liu et al. Clin Epigenet (2021) 13:124 Page 2 of 13 Keywords: Aortic dissection, DNA methylation, Epigenetics, Homeobox genes, Cell-free DNA, Epigenetic biomarker Background In this study, we explored the genome-wide DNA Toracic aortic dissection (TAD) is a devastating dis- methylation alteration in Stanford type A TAD ascend- ease with high mortality and severe complications. ing aortic tissues relative to healthy controls, identifed Based on aortic location, TAD can be clinically clas- numerous diferentially methylated regions (DMRs) and sifed into Stanford type A (ascending aorta) or type investigated the gene expression changes. In addition, we B (descending aorta). Patients with Stanford type A constructed a prediction model using DMRs identifed generally require emergent surgical repair, with about from aortic tissues on methylation signature of cell-free half experiencing mortality if treatment is not obtained DNA (cfDNA) for TAD identifcation. within three days of aortic tearing [1]. Although several genetic mutations have been found to be associated Results with some types of familial and syndromic TAD [2–4], Pathological alterations in dissected thoracic aortic tissues mechanisms pertaining to the initiation and progres- Ascending aortic tissues from Stanford type A TAD sion of TAD are poorly understood. Furthermore, lit- patients and healthy controls were collected, with the tle is known about the pathogenesis of sporadic TAD, adventitia removed to avoid any contributions from asso- which are the prevalent forms within the Chinese pop- ciated fatty tissues or endothelial cells. Histopathologic ulation. Recent evidence has suggested that life-style, examination revealed similar structural components environmental settings, and other risk factors (e.g., age between the TAD and control samples. Te dissected and hypertension) may all contribute to TAD onset and thoracic tissues from both groups were predominantly course [5–7]. However, the precise mechanisms that composed of smooth muscle cells (SMCs), collagens and modulate such intrinsic and extrinsic factors and the elastic fbers (Additional fle 1: Figures S1A and S1B). infuence they have on TAD development is still largely Despite both groups being predominantly comprised unknown. of SMCs, structural protein alterations associated with Since the high mortality rates of TAD, immediate pathology were observed. TAD samples showed an ele- early diagnoses are critical. Currently, TAD diagnoses vated collagen deposition (Additional fle 1: Figure S1C mostly rely on imaging techniques, such as computed and S1D) and a severe fragmentation of the elastic fbers tomographic angiography (CTA), magnetic resonance (Additional fle 1: Figures S1E and S1F) when compared imaging (MRI) or digital subtraction angiography to the control samples. (DSA), which may not be available in remote area or in certain emergent situation. Recent studies showed that Genome‑wide DNA methylation analysis of aortic tissues D-dimer and sST2 can be used in blood test for TAD To evaluate whether any epigenetic alterations are asso- diagnoses, but still with low sensitivity [8, 9]. Methyla- ciated with TAD pathogenesis, ascending aortic tissues tion pattern in cell-free DNA has showed high specifc- from six TAD (Stanford type A) and six healthy controls ity and sensitivity in some disease detections [10–12], were examined using WGBS. Following quality control and thus, it may be used as a potential biomarker for and data preprocessing, one control sample with bisulfte TAD diagnosis. conversion rate less than 90% (sample: N2) was elimi- Epigenetics is the study of heritable changes that nated. Among the 11 remaining samples, no signifcant regulate gene expression without altering the DNA global DNA methylation alterations were noted between sequence itself. Numerous recent studies have shown the TAD and control samples (Additional fle 1: Table S2). that altered epigenetic regulations, such as DNA meth- Based on these fndings, DMR analysis was performed ylation, are associated with the development of tumors to identify epigenetic diferences between the two groups. [13], metabolic diseases [14] and autoimmune disor- A total of 51,468 DMRs (22,318 hypermethylated and ders [15]. DNA methylation has also been shown to 29,150 hypomethylated) were identifed in the TAD sam- play a role in cardiovascular diseases (CVDs), such as ples relative to the controls, with 3314 of them (6.44%) heart failure [16], aberrant cardiovascular development located in promoter regions (1 to 2500 bp upstream of [17] and mineralization of the aortic valve [18], where transcription start site) (Fig. 1a). Among them, the per- extrinsic risk factors afect gene expression by alter- centages of hyper- and hypomethylated DMRs were simi- ing methylation and impacting downstream molecular lar in all of the eight examined gene annotation groups events. However, few studies have examined epigenetic (Fig. 1b). Te top 300DMRs (Additional fle 2: Table S3) regulations in TAD, especially for DNA methylation. included 14,365 CpGs with the median length of 1648 bp. Liu et al. Clin Epigenet (2021) 13:124 Page 3 of 13 Fig. 1 DNA methylation diferences between TAD and healthy control samples. a DMR percentages in diferent genomic components (promoters were defned as 1–2,500 bp upstream of transcription start site, alternative promoters were not included.). b Hypermethylated and hypomethylated DMR percentages in diferent genomic components. c Supervised clustering with the top
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