The Pharmacoepigenetic Connection

72 Current Pharmacogenomics and Personalized Medicine, 2020, Vol. 17, No. 2 Editorial

EDITORIAL The PharmacoEpiGenetic Connection

Ramón Cacabelos1,*

1International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, 15165, Corunna, Spain

Epigenetics is a discipline that studies heritable changes in gene expression without structural changes in the DNA sequence. Epigenetics is one of the most rapidly developing fields in the history of biology. The concept of epigenetics has evolved since Waddington defined it in the late 1930s, becoming a multifaceted contextual discipline with influence in evolution, speciation, functional genomics, transcriptomics, proteomics, metabolomics, and obviously in species-specific health and disease [1]. Epigenetics plays an important role in phenotypic variation in different species of animal and vegetal kingdom [2]. Epigenetic memory can persist across generations. A stress- induced signal can be transmitted across multiple unexposed generations leading to persistent changes in epigenetic gene regulation [3]. Epigenetic mechanisms contribute to phenotypic variation and disparities in morbidity and mor- tality [4]. Epigenetics acts as an interface between the genome and the environment, and the mechanistic changes associated with the epigenetic phenomena can also be considered a sophisticated form of intracellular and intercel- lular communication [5]. Epigenetics is an adaptive mechanism of developmental plasticity, a phenomenon of rele- vance in evolutionary biology and human health and disease, which enables organisms to respond to their environment based on previous experience without changes to the underlying nucleotide sequence [6]. Genetic variation correlates with phenotypes depending upon allele-specific genetic changes linked to gene expression, DNA methylation, histone marks, and miRNA regulation of proteomic and metabolomic processes [7]. Epigenomic modifications are involved in several pathological conditions; of major importance are those related with age and with significant health problems such as cardiovascular disorders, obesity, cancer, inflammatory disorders, asthma, allergy, and brain disorders. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms which include regulation of gene translocation, histone modifications, DNA methylation, DNA repair, transcription, RNA stability, alternative RNA splicing, protein degradation, gene copy number, and transposon acti- vation [8]. Epigenetic modifications are reversible and can potentially be targeted by pharmacological and dietary interventions [9]. The effects of drugs (pharmacokinetics and pharmacodynamics) and their therapeutic outcome in the treatment of a given disease are the result of a network of metabolomic events (genomics-transcriptomics-proteomics) associated with the binomial interaction of a chemical or biological molecule with a living organism. The clusters of genes currently involved in a pharmacogenomic process include pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes [10]. In practice, the expression of these genes is potentially modifiable (transcriptionally and/or post-transcriptionally) by epigenetic mechanisms which may alter (i) pathogenic events, (ii) receptor-drug interactions, (iii) drug metabolism (phase I and II enzymatic reactions), (iv) drug transport (influx-efflux across membranes and cellular barriers), and (v) pleiotropic events leading to unexpected therapeutic outcomes. The understanding of these mechanisms is the main focus of pharmacoepigenetics in order to optimize therapeutics and advance towards personalized medicine [11-16]. Unfortunately, the molecular mechanisms underlying the assembly, function and regulation of the epigenetic machinery are poorly understood, and most information in this regard is fragmented. This restrictive knowledge on epigenetic mechanisms represents an important limitation for defining the fundamentals of pharmacoepigenetics. Furthermore, the number of studies on pharmacogenetics and pharmacoepigenetics of current drugs for the treatment of common pathologies is still very limited; however, the available information is shedding light on the bene- fits that these complementary disciplines can provide to physicians and patients for the implementation of an effi- cient personalized medicine [16]. ______*Address correspondence to this author at the International Center of Neuroscience and Genomic Medicine, EuroEspes Biomedical Research Center, 15165, Corunna, Spain; E-mails: [email protected]; www.ramoncacabelos.org.

The epigenetic machinery is integrated by a cluster of interconnected elements that, in a coordinated manner, contribute to regulate gene expression at transcriptional and post-transcriptional levels. Classical epigenetic mechanisms include DNA methylation, histone modifications, and microRNA (miRNA) regulation. Canonical DNA me- thyltransferases (DNMTs)(DNMT1, DNMT3A and DNMT3B) are responsible for maintaining DNA methylation patterns, whereas DNA demethylation can be produced by at least 3 enzyme families: (i) the ten-eleven translocation (TET) family, mediating the conversion of 5mC into 5hmC; (ii) the AID/APOBEC family, acting as mediators of 5mC or 5hmC deamination; and (iii) the BER (base excision repair) glycosylase family involved in DNA repair. Chromatin remodeling and histone post-translational modifications are under the regulatory control of a pleiad of effectors. Post-translational modifications include methylation, acetylation, ubiquitylation, sumoylation, phosphory- lation, acylation (propionylation, butyrylation, 2-hydroxyisobutyrylation, succinylation, malonylation, glutarylation, crotonylation and β-hydroxybutyrylation), N-Glycosylation and O-GlcNAcylation, chaperonization, glutathionyla- tion, poly ADP-ribosylation, and peroxidation. Histone methylation is catalyzed by histone lysine methyltransferas- es (HKMT) and histone demethylation by histone lysine demethylases. Histone acetylation is catalyzed by 5 families of histone lysine acetyltransferases (KATs)(KAT2A/GCN5, KAT2B/PCAF, KAT6-8, CREBBP/CBP, EP300). Histone deacetylation is catalyzed by 4 classes of HDACs (class I, II, III, IV). O-GlcNAcylation is controlled by O- linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA). Ubiquitination consists of post-translational deposition of ubiquitin on proteins for degradation by proteases, and monoubiquitylation can be reversed by histone deubiquitinases [16]. Regulatory RNAs include two major categories: (i)(<200 nucleotides) microRNAs (miRNA), small interfering RNAs (siRNA), small nuclear RNAs (snRNA), piwi-interacting RNAs (piRNA), splice junction-associated RNAs; and (ii) long non-coding RNAs (lncRNAs) (>200 nucleotides), present in >8000 loci in the human genome: large intergenic non-coding RNAs (lincRNA), natural antisense transcripts (NATs), non-coding RNA expansion repeats, promoter-associated RNAs (PARs), enhancer RNAs (eRNAs), small activating RNAs (saRNAs, RNAa). Other important elements of the epigenetic machinery are transcription factors, transcriptional repressors, enhancers, trans- posable elements, and thousands of novel proteins involved in gene expression. This complex apparatus controls the genomic expression and orchestrates fecundity, embryo-fetal development, tissue maturation, organ conformation, body homeostasis, and aging. Epigenetic aberrations in the epigenetic machinery can lead to disease and mutations in readers, writers or erasers causing epigenetic Mendelian disorders. Since epigenetics is a reversible process, pharmacoepigenetics opens new avenues for epigenetic drug development and epitherapeutics [16]. Epigenetics is evolving at a very fast step for the past few years, creating great expectations in biology and medicine. It is very likely that many of our present concepts and interpretations on pathogenesis, molecular diagnosis and therapeutics of current human disorders will change in the near future with the advent of novel epigenetic data. Epigenetics adds complexity, diversity and evolutionary clues to the central dogma of biology by which gene expression entails the flow of genetic information from DNA to RNA and proteins. Epigenetic states help to shape differential utilization of genetic information and to preserve a long-lived memory of past signals [17]. The development of new techniques and procedures for epigenome editing and for simplification and interpreta- tion of results is necessary for a rapid translation of epigenetic knowledge into the clinic and for drug development. The completion of genome, epigenome, and transcriptome mapping demands precision biomolecular tools for DNA manipulation, chromatin structure reconstruction, and reshaping of gene expression patterns. Some molecular plat- forms for epigenetic editing have been developed [18]. Massive DNA sequencing has generated a large body of genomic, transcriptomic and epigenomic information that has provided clues for establishing three-dimensional (3D) genomic landscapes in various cells and tissues [19]. Epigenetics challenges conventional understanding of gene-environment interaction and intergenerational inher- itance and, probably, it might contribute to change some modern political ideologies and/or philosophical beliefs (atomistic individualism) [20]. Experiences of racial discrimination have been associated with poor health outcomes. Significant epigenetic associations between disease-associated genes and perceived discrimination, as meas- ured by the Major Life Discrimination (MLD) Scale, have been reported. Consequently, future health disparities research should include epigenetics in high-risk populations to elucidate functional consequences induced by the psychosocial environment [21]. Advances in the field of epigenetics will contribute to apply this knowledge in environmental health risk assessment [22]. Pathogens pose serious threats to human health, agricultural investment, and biodiversity conservation through the emergence of zoonoses, spillover to domestic livestock, and epizootic outbreaks. Understanding epigenetics of wildlife disease will enable more accurate risk assessment, reconstruction of transmission pathways, dis- 74 Current Pharmacogenomics and Personalized Medicine, 2020, Vol. 17, No. 2 Editorial cernment of optimal intervention strategies, and development of more effective and ecologically sound treatments in order to minimize damage to the host population and the environment [23]. Despite significant technological advances for epigenetic profiling, there is still a need for a systematic understanding of how epigenetics shapes cellular circuitry and disease pathogenesis. The development of accurate computational approaches for analyzing complex epigenetic profiles is essential for disentangling the mechanisms underlying cellular development, and the intricate interaction networks determining and sensing chromatin modifications and DNA methylation to control gene expression. Computational epigenetics is an essential aid for the implementation of epigenetic procedures in the clinical setting and pharmacoepigenetics [24]. The physicians of the 21st century have to adapt their mentality and aptitude to understand new concepts, new interpretations of disease pathology, new biomarkers for an early (or presymptomatic) diagnosis, and new strategies for personalized medicine in order to efficiently serve their patients and preserve the health conditions of the population [16,25,26].

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