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For Peer Review Page 33 of 135 Arthritis & Rheumatology Mitochondrial DNA (mtDNA) haplogroups J and H are differentially associated with the methylation status of articular cartilage: potential role in apoptosis and metabolic and developmental processes Estefanía Cortés-Pereira1&, Juan Fernández-Tajes2&, Mercedes Fernández-Moreno1,3, María E Vázquez-Mosquera1, Sara Relaño1, Paula Ramos-Louro1, Alejandro Durán-Sotuela1, Andrea Dalmao- Fernández1, Natividad Oreiro1, Francisco J Blanco1*¶, Ignacio Rego- Pérez1*¶ 1) Servicio de Reumatología.For InstitutoPeer de Investigación Review Biomédica de A Coruña (INIBIC). Complexo Hospitalario Universitario de A Coruña (CHUAC), Sergas. Universidade da Coruña (UDC). As Xubias, 15006. A Coruña, España 2) Wellcome Trust Centre for Human Genetics. McCarthy´s group. University of Oxford. Roosevelt Drive, Oxford, OX3 7BN, UK 3) Centro de Investigación Biomédica en Red, Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN) *Corresponding authors E-mail: [email protected] (IRP) and [email protected] (FJB) ¶These authors contributed equally to this work &These authors also contributed equally to this work 1 John Wiley & Sons Arthritis & Rheumatology Page 34 of 135 ABSTRACT Objective To analyse the influence of mitochondrial genome variation on the DNA methylome of articular cartilage Methods DNA methylation profiling was performed from data deposited in the NCBI Gene Expression Omnibus (GEO) database (accession number GSE43269) consisted in the data of 14 haplogroup J cartilages and 20 H cartilages. Subsequent validation was performed in an independent subset of 7 haplogroup J cartilages and 9 H cartilages by RNA-seq. Correlated genes were validated by real-time PCR in an independent cohort of 12 J cartilages and 12 H cartilages. Appropriate analytical analyses were performed using R bioconductor and qBase plus software, andFor gene ontologyPeer analyses Review were conducted using DAVID v6.8 Results DNA methylation profiling revealed 538 differentially methylated loci (DML) between H and J cartilages, whilst whole-transcriptome profiling identified 2384 differentially expressed genes between H and J cartilages. 17 genes showed an inverse correlation between methylation and expression. In terms of gene ontology, negative correlations between methylation and expression were also detected between H and J cartilages; highlighting a significantly enhanced and repressed apoptotic process in H and J cartilages respectively, as well as a significant enrichment of genes related to metabolic process and regulation of gene expression, in H cartilages, and to developmental process in J cartilages. Conclusion Mitochondrial DNA variation differentially associates with the methylation status of articular cartilage by acting on key mechanisms involved in OA, such as apoptosis, metabolic and developmental processes. 2 John Wiley & Sons Page 35 of 135 Arthritis & Rheumatology INTRODUCTION Osteoarthritis (OA) is a chronic progressive disorder that involves movable joints and is characterised by cell stress and extracellular matrix degradation initiated by micro- and macro-injuries that activate maladaptive repair responses including pro-inflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal tissue metabolism) followed by anatomical and/or physiologicalFor derangements Peer Review(characterised by cartilage degradation, bone remodelling, osteophyte formation, joint inflammation and loss of normal joint function) that can culminate in illness (1). OA is a heterogeneous disease, with a combination of modifiable factors, such as body mass index or joint injury, and non-modifiable factors like age, gender or genetics. In recent years, the study of epigenetics in OA attracted increasing interest. The term epigenetics refers to heritable changes in gene expression without changes in the DNA sequence, either by affecting gene transcription or by acting post-transcriptionally. Among the best characterized epigenetic mechanisms, DNA methylation stand out. It has been proposed that DNA methylation is involved in the phenotypic modulation that articular chondrocytes experience during the development of OA, leading to an over-expression of cartilage- degrading enzymes and inflammatory mediators, breaking the homeostatic balance towards extracellular matrix degradation and playing a decisive role in the progression of the disease (2, 3). 3 John Wiley & Sons Arthritis & Rheumatology Page 36 of 135 Initial DNA methylation studies in OA were based on the study of specific CpG sites within the promoter region of OA-related genes, mainly cartilage-degrading enzymes (2, 4-7). More recently, genome- wide DNA methylation analyses in OA have also been performed. These studies included the analysis of the methylome of cartilage/chondrocyte, the subchondral bone as well as human mesenchimal stem cells (hMSCs) from femoral heads of patients with hip fractures (8). FromFor these Peer studies, Reviewinteresting conclusions can be drawn; on the one hand, hip and knee cartilage show different DNA methylomes (9) and even OA patients with the same affected joint can have different methylomes too; more specifically, a subgroup of OA patients with altered methylome in inflammation-related genes was independently identified (9, 10). On the other hand, the presence of an epigenetic phenotype associated with eroded OA subchondral bone similar to that of overlying eroded OA cartilage was also suggested (11), and hMSCs from OA patients with hip fractures showed accelerated methylation aging and enhanced proliferation of the osteogenic drivers RUNX2/OSX (12). Altogether, these works evidence the complexity of OA that includes complex genetic-epigenetic interactions and therefore further efforts must be done in order to clarify the role played by epigenetics in this disease (13). Mitochondria and the mitochondrial DNA (mtDNA) haplogroups play a role in the pathogenesis of OA (14). Specifically, the mtDNA haplogroups influence the prevalence of OA in different geographic populations (15-17) as well as the radiographic progression and 4 John Wiley & Sons Page 37 of 135 Arthritis & Rheumatology cartilage integrity over time in patients of the progression subcohort of the Osteoarthritis Initiative (18, 19). A recent meta-analysis involving more than 3000 subjects concluded that mtDNA haplogroups significantly influence the rate of incident knee OA; specifically, those subjects harboring haplogroup J show a significant decreased risk of developing incident knee OA at 8 years compared with subjects harboring haplogroup H, a different haplogroup in terms of ROS and ATP production, mitochondrialFor Peer metabolism Review and apoptosis (20). The function of the mitochondria is controlled by the nucleus by means of an “anterograde regulation”, a mechanism that regulates both mitochondrial biogenesis and activity to meet the needs of the cell; on the other hand, mitochondria and mtDNA variation maintain partial regulatory signaling control over the nuclear epigenome, modulating the expression of nuclear genes through a “retrograde regulation”, a response signaling mechanism that leads to the modification of cellular function by reprogramming its metabolism (21, 22). The role of this bidirectional communication between nucleus and mitochondrion is not only to maintain cellular homeostasis, but also regulate the adaptation to a wide range of stressors (23). In the light of these evidences and, given the demonstrated role of the mitochondria and mtDNA variation in OA, in this study we analyze the methylation data of cartilage samples carrying the mtDNA haplogroups H and J from our previously published genome-wide methylation assay (10) in order to check the influence of the mtDNA haplogroups on the DNA methylome of articular cartilage. 5 John Wiley & Sons Arthritis & Rheumatology Page 38 of 135 MATERIALS AND METHODS DNA methylation profiling. DNA methylation profiling was performed using previous methylation raw data deposited in the NCBI Gene Expression Omnibus (GEO) database (http://www.ncbi.nlm.nih.gov/geo/), with accession number GSE43269 (10). These data were obtained using the Infinium HumanMethylation27 beadchip (Illumina, San Diego, CA, USA), which allows interrogation of 27,578 highly informativeFor PeerCpG sites Review located within the proximal promoter regions of 14,495 genes and 110 microRNAs. We collected the methylation data from 14 J cartilage samples and 20 H (Table 1) to subsequently perform the appropriate differential analyses between these two haplogroups. Data filtering, normalization and analysis of methylation data. The detection p-values measure the difference in signal intensities between the interrogated CpG site and those from a set of 16 negative control probes embedded in the assay. Therefore, those samples with a detection p-value greater than 0.05 in more than 25% of all probes were considered as not significantly different from background noise, and removed from subsequent analyses as an extra quality control measure. Besides, those probes that were designed for sequences on X and Y chromosomes were also excluded. We used M-value defined by Lumi and Methylumi package (R, Bioconductor) for differentially methylated analysis between mtDNA haplogroups H and J. M-value, which is the log2 ratio of methylated probe intensity and unmethylated probe intensity, is a method used to 6 John Wiley & Sons Page 39 of 135 Arthritis & Rheumatology measure the methylation levels and is homoscedastic
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