Table 1.
A glossary of key epigenetic terms and biological function of genes involved in pathways discussed in this review
| Gene names and key terms | Biological function and definition |
|---|---|
| Epigenetic terms | |
| DNA-methylation | DNA-meth is the covalent addition of a methyl group to the 5th carbon of a Cytosine (C) base, resulting in a 5-methylcytosine (5-mC) base. Epigenetic is the major process by which the environment can alter gene expression |
| Candidate gene approach | Explores methylation on certain genes of interests based on a priory hypothesis. It often examines whether DNAm changes in different CG sites within specific genes are related to a particular phenotype. |
| Epigenome-Wide Association Studies | Examines the association of DNAm changes (otherwise called methylome-wide association studies (MWAS)) across the entire genome for a particular phenotype, using a hypothesis-free paradigm. EWAS have been performed with increasingly powerful techniques and have moved from pioneer CpG-island microarrays studies that interrogated around 12.000 sites across the DNA (Mill et al., 2008) to more advanced techniques such as Infinium MethylationEPIC BeadChip, that covers more than 850 000 CpG methylation sites (Yong et al., 2016). |
| Histone acetylation studies | Histone acetylation is a dynamic epigenetic modification that functions in the regulation of DNA-templated reactions, such as transcription. This lysine modification is reversibly controlled by histone (lysine) acetyltransferases and deacetylases. |
| Methylome-wide association studies (MWAS) | Test a genome-wide set of methylation sites for association with an outcome of interest. |
| Serotoninergic pathway | |
| SLC6A4 | Regulated serotonergic signalling via transporting 5-HT from synaptic spaces into presynaptic neurons. SLCA2 is involved in the recapture of the Norepinephrine |
| 5-HTR (1A, 2A, 2B 3A, 5A) | These genes encode for the receptors for the neurotransmitter serotonin |
| A (MAOA) | One of two neighbouring gene family members that encode mitochondrial enzymes which catalyse the oxidative deamination of amines, such as dopamine, norepinephrine, and serotonin |
| Dopaminergic pathway | |
| DRD (2a, 3, 4) | Encode different subtypes of the dopamine receptor |
| COMTa(D1) | Encodes for Catechol-O-methyltransferase enzyme, which catalyses the transfer of a methyl group from S-adenosylmethionine to catecholamines, including the neurotransmitters dopamine, epinephrine, and norepinephrine important in the degradation of Dopamine (DA) |
| DAT1a | The dopamine transporter is implicated in a number of dopamine-related disorders, including attention deficit hyperactivity disorder, bipolar disorder, clinical depression, alcoholism, and substance use disorder |
| FAM63B | Involved in four networks regulated by miRNA, three of which are linked to neuronal differentiation and dopaminergic gene expression |
| SLC6A3 | Provides instructions for making a protein called the dopamine transporter or DAT |
| Glutamatergic/GABAergic pathway | |
| GAD1 | Encodes one of several forms of glutamic acid decarboxylase, an enzyme which is responsible for catalysing the production of gamma-aminobutyric acid from L-glutamic acid |
| PVALB | Encodes for Parvalbumin protein, essential for neural synchronisation in some neurons in the CNS |
| GRIN1 (2,2B 3B, D1) | The protein encoded by this gene is a critical subunit of N-methyl-D-aspartate receptors, members of the glutamate receptor channel superfamily. It plays an important role in the plasticity of synapses |
| GRIA 2, 3 | Encodes for the Glutamate Ionotropic Receptor AMPA Type Subunit 2 and 3 Glutamate receptors, which are the predominant excitatory neurotransmitter receptors in the mammalian brain |
| MARLIN-1 | (synonym of JAKMIP1) codes for a protein that may play a role in the microtubule-dependent transport of the GABA-B receptor |
| KCNJ6 | Encodes a member of the G protein-coupled inwardly-rectifying potassium channel family of inward rectifier potassium channels. This type of potassium channel allows a greater flow of potassium into the cell than out of it and thus regulates circuit activities in neural cells. Expressed in GABAergic synapses |
| HELT | Protein Coding gene involved in DNA-binding transcription factor activity and protein dimerisation activity. It is a transcriptional repressor gene which is known to function as a selector gene that determines GABAergic over glutamatergic fate in the mesencephalon |
| GRIK2 | Codes for the Glutamate Ionotropic Receptor Kainate Type Subunit 2. Glutamate receptors are the predominant excitatory neurotransmitter receptors in the mammalian brain |
| SLC6A12 | Transports betaine and GABA. May have a role in the regulation of GABAergic transmission in the brain through the reuptake of GABA into presynaptic terminals, as well as in osmotic regulation. |
| GABBR1, 2 | Encodes a receptor for GABA that functions as a heterodimer with GABA(B) receptor 1 and 2. Defects in this gene may underlie brain disorders such as schizophrenia and epilepsy. |
| GRIN3B | The protein encoded by this gene is a subunit of an N-methyl-D-aspartate (NMDA) receptor. The encoded protein is found primarily in motor neurons, where it forms a heterotetramer with GRIN1 to create an excitatory glycine receptor. Variations in this gene have been proposed to be linked to schizophrenia |
| Neurogenesis | |
| RELN | This gene encodes a large secreted extracellular matrix protein (Reelin) thought to control cell-cell interactions critical for cell positioning and neuronal migration during brain development. expressed in GABAergic interneurons |
| BDNF | Encodes the brain-derived neurotrophic factor (BDNF), a protein involved in promoting the survival, growth and differentiation of new neurons and synapses |
| POU5F1, POU6F2. POU3F1 | Encodes a transcription factor protein that binds to the octamer motif (5-ATTTGCAT-3) and controls myelination (thought to be involved in embryogenesis and neurogenesis) |
| NPDC1 | Encored for a protein that Suppresses oncogenic transformation in neural and non-neural cells and down-regulates neural cell proliferation. Might be involved in transcriptional regulation |
| PI3K | Phosphatidylinositol 3-kinases, are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking |
| CUX1a | Encodes a member of the homeodomain family of DNA binding proteins that regulates gene expression, morphogenesis, and differentiation and it also plays a role in cell cycle progression |
| CLMNa | Encodes calmin (calponin-like transmembrane domain protein) |
| SENP7a | Encodes sentrin-specific protease 7 |
| Immune system and inflammation | |
| ZC3H12D | It is a Protein (Zinc Finger CCCH-Type Containing 12D) Coding gene, which in association with ZC3H12A enhances the degradation of interleukin IL-6 mRNA level in activated macrophages, among other functions |
| TCF3 | This gene encodes a member of the E protein (class I) family of helix-loop-helix transcription factors. E proteins play a critical role in lymphopoiesis, and the encoded protein is required for B and T lymphocyte development, among other functions |
| IKZF4 | Members of the Ikaros family of transcription factors, which includes Eos, are expressed in lymphocytes and are implicated in the control of lymphoid development |
| YOD1 | Protein ubiquitination controls many intracellular processes, including cell cycle progression, transcriptional activation, and signal transduction, involved in IL-1 signalling to NF-κB |
| IL17RA | Code for Interleukin 17A (IL17A), which is a proinflammatory cytokine secreted by activated T-lymphocytes |
| TLR1 (3) | Encodes Toll-Like Receptor 1, family which plays a fundamental role in pathogen recognition and activation of innate immunity |
| TNFRSF13C | TNF Receptor Superfamily Member 13C, a membrane protein of the TNF receptor superfamily which recognises BAFF, an essential factor for B cell maturation and survival |
| HERC5 | This gene is a member of the HERC family of ubiquitin ligases and encodes a protein with a HECT domain and five RCC1 repeats. Pro-inflammatory cytokines upregulate expression of this gene in endothelial cells |
| FCGR2B | One of the genes thought to influence susceptibility to several autoimmune diseases in humans inhibiting the functions of activating FcγRs, such as phagocytosis and pro-inflammatory cytokine release |
| PIK3R3 | Plays an important role in the regulation of cellular lipid metabolism |
| INPP5D | Encodes Src homology 2 (SH2) domain-containing inositol polyphosphate 5-phosphatase 1 (SHIP1) that functions as a negative regulator of cell proliferation and survival |
| FCGR2C, 2B | Encodes one of three members of a family of low-affinity immunoglobulin gamma Fc receptors found on the surface of many immune response cells and involved in phagocytosis |
| IGHA1 | Encodes a constant (C) segment of Immunoglobulin A heavy chain that plays a critical role in immune function in the mucous membranes |
| FCAR | Codes for the transmembrane receptor FcαRI, also known as CD89 (Cluster of Differentiation 89), that plays a role in both pro- and anti-inflammatory responses |
| CD224 | This gene is a human gamma-glutamyltransferase catalyses the transfer of the glutamyl moiety of glutathione to a variety of amino acids and dipeptide acceptors |
| LAX1 | A membrane-associated adaptor protein mainly expressed in B cells, T cells, and other lymphoid-specific cell types |
| TXK | A member of Tec family nonreceptor tyrosine kinase, is expressed on Th1/Th0 cells, and Txk regulates specifically IFN-gamma gene expression |
| PRF1 | Encodes perforin a pore-forming cytolytic protein found in the granules of cytotoxic T lymphocytes (CTLs) and natural killer cells (NK cells) |
| CD7 | Encodes a transmembrane protein which is a member of the immunoglobulin superfamily found on thymocytes and mature T cells that plays an essential role in T-cell interactions and also in T-cell/B-cell interaction during early lymphoid development |
| MPG | Encodes N-methylpurine DNA glycosylase a specific type of DNA glycosylase involved in the recognition of a variety of base lesions, including alkylated and deaminated purines, and initiating their repair via the base excision repair pathway |
| MPOG | A member of the XPO subfamily of peroxidase enzyme most abundantly expressed in neutrophil granulocytes |
| MARC2a | The protein encoded by this gene is an enzyme found in the outer mitochondrial membrane that reduces N-hydroxylated substrates |
| CEMIPa | Cell migration-inducing and hyaluronal-binding protein, known as KIAA1199, has been shown to bind hyaluronic acid and catalyse its depolymerisation its depolymerisation independently of CD44 and hyaluronidases |
| Oxidative stress | |
| GGT6 | Encored for a gamma-glutamyltransferase, that plays a key role in glutathione homoeostasis by providing substrates for its synthesis |
| GSTM5 | (Glutathione S-Transferase Mu 5), important for glutathione homoeostasis |
| Hypothalamus pituitary adrenal axis pathway | |
| NR3C1 | Encodes the human glucocorticoid receptor protein, which is the receptor to which cortisol and other glucocorticoids bind |
| miR124 | A microRNA that targets NR3C1 |
| FKBP5 (2, 1B) | Encodes the FK506 binding protein, a member of the immunophilin protein family which may play a role in immunoregulation and basic cellular processes involving protein folding and trafficking |
| SKA2 | Encodes for a component of the spindle and kinetochore-associated protein complex, which is a protein complex involved in regulating chromosomal segregation. SKA2 is important in facilitating GR nuclear transactivation. |
| Cannabinoid system | |
| CNR1 and CNR2a | Encodes the cannabinoid receptor gene |
| Other genes | |
| DNMTS | This gene encodes an enzyme that transfers methyl groups to cytosine nucleotides of genomic DNA |
| OXTR | Encodes oxytocin, which is a neuropeptide hormone produced by the hypothalamus and released into systemic circulation by the posterior pituitary |
| Tobacco signature genes | |
| AHRRa | The protein encoded by this gene participates in the aryl hydrocarbon receptor (AhR) signalling cascade, which mediates dioxin toxicity, and is involved in the regulation of cell growth and differentiation |
| F2RL3a | Encodes a member of the protease-activated receptor subfamily, part of the G-protein coupled receptor 1 family of proteins. This receptor plays a role in blood coagulation, inflammation and response to pain |
| GFI1 | Encodes a nuclear zinc finger protein that functions as a transcriptional repressor. This protein plays a role in diverse developmental contexts, including haematopoiesis and oncogenesis |
| MYO1G | Is a plasma membrane-associated class I myosin that is abundant in T and B lymphocytes and mast cells.. This myosin is required during immune response for detection of rare antigen-presenting cells by regulating T-cell migration |
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genes related to cannabis use.