# The Role of Epigenetics in Periodontal and Systemic Diseases and Smoking: A Systematic Review
## 1 Introduction  
Periodontitis is a biofilm-induced condition that affects tooth-supporting tissues [1], which consists mainly of Gram-negative, anaerobic, and micro-aerophilic bacteria that can colonize the sub-gingiyal tissues [2; 3]. The bacterial biofilm induces an inflammatory host response, which is influenced by environmental, genetic, and epigenetic factors [4; 5; 6]. Epigenetic factors refer to alterations in the gene expression that are not encoded in the DNA sequence [7; 8], which include chemical alterations of the DNA and histones, resulting in the remodeling of the chromatin and activation or inactivation of a gene [9; 10; 11].  
To date, the most recognized epigenetic mechanism is DNA methylation, which is regulated by DNA methyltransferases (DNMIs), resulting in the covalent addition of methylgroups to the 5' position at the base cytosine (5 mC) and [12]. DNA methylation results in gene silencing [8; 13]. Another form of epigenetic change is post-translational modifications of histones, which form the building blocks of the chromatin (i.e., nucleosomes). The most studied histone modification is histone acetylation. Histone acetylation is linked with transcriptional activation [14] and is regulated by histone acetyltransferases (HATs) that add acetyl groups to histones and histone deacetylases (HDACs) that remove acetyl groups [15]. While DNA methylation and histone modifications are linked [12; 15], DNA methylation offers a more stable form of gene regulation [16].  
The epigenome is dynamic throughout life and can be influenced by environmental and lifestyle factors. Unlike the human genome, the epigenome can be reversed; hence, epigenetic mechanisms have therapeutic potential for improving personalized drug therapy [17]. Moreover, understanding the role of epigenetic in periodontal diseases and systemic diseases could potentially improve wound healing and periodontal tissue regeneration [10].  
Due to this dynamic nature of the epigenetic mechanisms, they have been thoroughly investigated in pathological conditions, such as rheumatoid arthritis (RA) [18], metabolic syndrome [19], and cancer [20]. As known, periodontitis shares pathogenesis pathways with RA [21; 22] and is associated with metabolic syndrome [23] and an increased risk of several cancers [24]; therefore, studies that investigate the epigenetic modifications in periodontitis patients with these systemic diseases are emerging. Similarly, smoking contributes to the complex network of interactions between an individual's immune response, bacterial biofilm [25], and epigenetics [26]. As such, smoking affects the host defense system [27; 28; 29] and the chromatin structure [26]. Since smoking is a well-established risk factor of periodontitis [30] and affects the chromatin structure [26], recent studies have assessed the epigenetic pattern in smoking periodontitis patients, as well.  
In this context, we have developed a systematic review to thoroughly present the potential interactions between epigenetics and periodontal diseases associated with systemic diseases/smoking, which would give a better understanding of this topic to both researchers and clinicians.