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Title:The role of epigenetic factors in human disease ABSTRACT: Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Research has shown that epigenetic mechanisms provide an “extra” layer of transcriptional control that regulates how genes are expressed.

These mechanisms are critical components in the normal development and growth of cells and control gene expression in a potentially heritable way,also play role in health and disease. The epigenetic modification of interest include DNA methylation, histone modificatin and related transcription inactivation associated with chromatin architecure. Epigenetic abnormalities have been found to be causative factors in cancer, genetic disorders and pediatric syndromes as well as contributing factors in autoimmune diseases and aging. As a results, epigenetics therapy has become an interesting phenomenon to counteract the epigenteic modifications that lead to various human disorder. Keywords: Epigenetics, epigenetics modifications , epigenetics disorders, epigenetics therapy.

INTRODUCTION: In the early 1940s epigenetics was defined by Conrad Waddington in the early 1940s as the branch of biology that studies the causal interactions between genes and their products which bring the phenotype into being 1. Currently, epigenetics is defined as the study of changes in gene function that are inheritable and that do not entail a change in DNA sequence 2. Research has shown that epigenetic mechanisms provide an “extra” layer of transcriptional control that regulates how genes are expressed 3. Epigenetic mechanisms are inheritable thus the epigenetic markers have the ability to persist during development and potentially be transmitted from offspring to offspring.

These mechanisms play an important role in regulation of gene and miRNA expression, DNA-protein interactions, cell differentiation, embryogenesis, X-chromosome inactivation, and genomic imprinting 4. One of the major functions of epigenetics is gene regulation. Gene regulation plays an important role in determining individual gene function and activity, the sets of genes which are functional in each specific cell type, cell type development and differentiation, and metabolic plasticity of the cell that allows it to adapt itself to environmental changes. However, epigenetics is not only the determinant of gene function. There are intrinsic components that are stable over time and are the same in each cell type.

These intrinsic components, which include polymorphism and mutations, are among the mechanisms that affect gene expression. Also, the environmental factors (virus, hormones, nutrition, and chemicals) influences epigenetics and thus, the intrinsic component altering gene function 5. Fig 1: Epigenetic factors influencing human development and growth.refThe interaction between environment and epigenetics is only one of the mechanisms by which a large range of different phenotypes arise from the same genotype,such as in the case of monozygotic twins 6,7. Although, epigenetics does not involve changes in DNA sequence but is nevertheless able to in?uence heritable gene expression through a number of processes such as DNA methylation, histone modi?cations of chromatin and non-coding RNAs, each of which alters how genes are expressed without altering the underlying DNA sequence.8. DNA methylation is mediated by DNA methyltransferase enzymes at CpG sites. It can also decrease gene expression by reducing the binding of transcription factors or increasing the binding of methyl-CpG binding proteins10,11,12,.Histone acetylation, particularly in lysine residues of histone tails, is an important histone modification that can accelerate binding transcription factors and then gene expression beside DNA demethylation13,12.

The formation of miRNA begins in nucleus and continues in cytosol that can perform a mechanism to regulate gene expression in mRNA level 14. Collectively, epigenetic processes are now generally accepted to play a key role in human diseases. As the knowledge of epigenetic mechanisms in human diseases expands, it is expected that approaches to disease prevention and therapy using epigenetic interventions will also continue to develop and may eventually become mainstays in disease management. Epigenetic modifications Researchers have identified mainly three types of epigenetic pathways: DNA methylation, histone modification, and non-coding RNA-mediated pathways. These epigenetic pathways related with each other to regulate expression of genes.

15.The general concepts of these pathways are briefly outlined below: Fig 2: Epigenetic mechanisms DNA methylaion: DNA methylation was the first recognized epigenetic modification, which occurs by the covalent addition of the methyl group at the 5-carbon of the cytosine ring resulting in 5-methylcytosine (5-mC), also informally known as the “fifth base” of DNA. It is highly specific and always happens in a region in which a cytosine nucleotide is located next to a guanine nucleotide that is linked by a phosphate; this is called a CpG site16,17,18. CpG sites are methylated by one of three enzymes called DNA methyltransferases (DNMTs)16,18.DNA methylation are common contributors to disease. For example, diabetes, schizophrenia, autism and cancer, asthe Angelman, Silvere Russell, Pradere Willi and Beckwithe Wiedemann syndromes and many other diseases have also been associated with DNA methylation.. Abnormalities of the enzymes that mediate DNA methylation can also contribute to disease as ill by the rare Immunode?ciencyeCentromere instabilityeFacial anomalies (ICF) syndrome caused by mutations in DNA methyltransferase 3B (DNMT3B).

Rett syndrome, related to mutations in the methyl-binding domain (MBD) protein, MeCP2, leads to dysregulations in gene expression and neurodevelopmental disease.Perhaps most commonly, DNA methylation can often contribute to cancer either through DNA hypo- or hypermethylation. DNA hypomethylation leads to chromosomal instability and can also contribute to oncogene activation, both common processes in oncogenesis, and DNA hypermethylation is often associated with tumor suppressor gene inactivation during tumorigenesis.19,20 . Fig 3: Histone modification: Histone modification is a covalent post-translational modification (PTM) to histone proteins which includes methylation, phosphorylation, acetylation, ubiquitylation, and sumoylation. The PTMs made to histones can impact gene expression by altering chromatin structure or recruiting histone modifiers.

Histone proteins act to package DNA, which wraps around the eight histones, into chromosomes. Histone modifications act in diverse biological processes such as transcriptional activation/inactivation,chromosome packaging, and DNA damage/repair. Fig:4 Histone modifications Histone modi?cations frequently contribute to disease development and progressions and histone acetylation or deacetylation are the most common histone modi?cations involved in diseases. Aberrations in histone modi?cations can signi?cantly disrupt gene regulation, a common factor in disease, and could potentially be transmissible across generations 21. Non coding RNAs: Non-coding RNAs(ncRNA) is a functional RNA molecule that is transcribed from DNA but not translated into proteins and an emerging area of epigenetics and alternations in these RNAs, especially microRNAs (miRNAs), contribute to numerous diseases. miRNAs can inhibit translation of mRNA if the miRNA binds to the mRNA, a process that leads to its degradation, or the miRNA may partially bind to the 30 end of the mRNA and prohibit the actions of transfer RNA 22.

Although miRNAs have been associated with a number of diseases such as Crohn’s disease 23, their role in tumorigenesis is now established and is considered to be a frequent epigenetic aberration in cancer. . Figure 5. Overview of non-coding RNAs Epigenetics and Human disease: Alterations in epigenetic pathways have been shown to be implicated in common human diseases.An overview are given below to illustrate the of epigenetic modification in human disease. Fig Relationship Between Human Diseases and Epigenetic Modi?cations ref 24 CANCER EPIGENETICS The first human disease to be linked o epigeneics was cancer.25. The cancer epigenome is characterized by global changes in DNA methylation, histone modification patterns and chromatin-modifying enzymeexpression profiles2627, which play important roles in cancer initiation and progression.

Figure 6: Schematic presentation of epigenetics in breast cancer DNA methylation was the first epigenetic alteration to be observed in cancer cells28. Hypermethylation of CpG islands at tumour suppressor genes switches off these genes, whereas global hypomethylation leads to genome instability and inappropriate activation of oncogenes and transposable elements29.It appears that genomic DNA methylatio levels, which are maintained by DNMT enzymes, are delicately balanced within cells; over-expression of DNMTs is linked to cancer in humans, and their deletion from animals is lethal2830. A number of factors can influence the DNA methylation levels of a cell without requiring a change in genomic DNA sequence such aging,diet, and environment. Aging: With aging in certain tissues there is a general tendency for the genome to become hypomethylated whereas certain CpG islands become hypermethylated, a situation reminiscent of that found in many cancer cells 31.    Diet:  Nutrition supplies the methyl groups for DNA (and histone) methylation via the folate and methionine pathways.  Importantly, mammals cannot synthesise folate or methionine and so a diet low in these compounds leads to alterations in DNA methylation. These changes have been associated with cancer30. Environment:  Agents such as arsenic and cadmium can have profound effects on DNA methylation.  Arsenic causes hypomethylation of the ras gene whereas cadmium induces global hypomethylation by inactivating DNMT1ref 32,33 Histone modi?cations The histone N-terminal tails are crucial in helping to maintain chromatin stability and they are subject to numerous modifications.

Most modifications have some role to play in transcriptional regulation and so each has the potential to be oncogenic if deregulated deposition leads, for example, to loss of expression of a tumour suppressor gene. 34.35 Histone acetylation tends to open up chromatin structure. Accordingly, histone acetyltransferase (HATs) tend to be transcriptional activators whereas histone deacetylases (HDACs) tend to be repressors.34,35 All lysine methyltransferases that target histone N-terminal tails contain a so-called SET domain.This domain possesses lysine methyltransferase activity and numerous SET domain-containing proteins are implicated in cancer.36,37. H3S10 and H3S28 are phosphorylated at mitosis – a crucial part of the cell cycle; misregulation here is often associated with cancers.34,35 MicroRNAs (miRNAs) are central to many cellular functions and they are frequently dysregulated during oncogenesis In fact, Micro RNAs affect the expression of genes linked to the cell cycle and expression of miRNAs is altered in cancer cells.

miRNA profiling has also proved to be a very useful aid to classifying different cancer types38. Epigenetics of neurological disease The neurobehavioral diseases, recently named brain diseases are associated with diseases such as Huntington’s disease (HD) along with common multifactorial and multilevel diseases with genetic and environmental factors, such as schizophrenia (SZ), autism spectrum disorder (ASD), and bipolar disease (BD) .Common neurodegenerative diseases associated with aging are dementia, Alzheimer’s and Parkinson’s diseases39.Abnormal functioning of the epigenetic mechanisms causes many congenital neurobiological disorders. Environmental factors, such as nutrition, drugs, and psychological pressure, have been viewed to result to epigenetic changes. Epigenetic changes caused by environmental stress in adolescence will persist through adulthood and should be transmitted across generations 40-42 fig 7 AUTOIMMUNITY AND EPIGENETICS Autoimmune diseases are a complex group of diseases that do not have the same epidemiology, pathology, or symptoms but do have a common origin 43.Epigenetic profiles in cells are influenced by environmental conditions additionally as by aging, reinforcing the observed relationship between age, environmental factors, and pathology development. Additionally, women are characterized by a more incidence of autoimmune diseases, probably related with chromosome inactivation, 44 fig 8 DNA methylation is the most widely studied mechanism in autoimmune diseases. Several studies done so far have found that some diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

have global hypomethylation in the cells they target in promoter regions of DNA . 1.6 Human imprinting disorders Genomic imprinting is the e phenomenon initially discovered in human disorders. In an imprinted gene, one out of the two parental alleles is active and the other allele is inactive due to epigenetic mechanisms such as DNA methylation. Therefore, mutations in the active allele or deletion of the active allele of the imprinted gene results in no expression.

This has been found in autistic disorders, Angelman syndrome, and PradereWilli syndrome 45 Other conditions involving imprinting include Beckwith-Wiedemann syndrome, Silver-Russell syndrome, and pseudohypoparathyroidism.46Transient neonatal diabetes mellitus can also involve imprinting.47The “imprinted brain theory” argues that unbalanced imprinting may be a cause of autism and psychosis, fig 9 1.7 Epigenetic of obesity Obesity is one of the chronic debilitating multisystem diseases due to environmental influences on present living style, such as food and exercise, on overweight liability indicate a strong role for non- genetic factors. Few overweigh disorders and the modulation of phenotype by diet in mouse models have hinted at these epigenomic possibilities.48 fig 10 Diabetes and the epigentic connection Type-2 diabetes is a polygenic, multifactorial disease characterized by hyperglycemia due to impaired insulin secretion and action. Epigenetic mechanisms, further as polymer methylation and histone modifications, may provide a link between environmental factors and also the genome, and thereby affect the risk for type-2 diabetes. Current research has shown that non-genetic risk factors for type-2 diabetes, like aging, overweight, and less immunity power, are associated with epigenetic changes in target tissues for the disease 49. Moreover, patients with type-2 diabetes show differential DNA methylation compared with non-diabetic individuals, proposing that epigenetic mechanisms may play a main role within the pathogenesis for the disease 50 fig 11 Model proposing a role for epigenetic mechanisms in the pathogenesis of type 2 diabetes. 1.9 Epigenetics and allergic disorders Allergic diseases such as asthma, allergic rhinitis, and eczema has risen at an alarming rate over the past 4-5 decades 51,52.

This has been associated with the marked environmental changes associated with transition to more modern lifestyles, There is a evidence that the effects of environmental change are potentially greatest during critical periods of life, when epigenetic modi?cations in immune gene expression can alter subsequent disease susceptibility. While there is also solid evidence that epigenetic machinery regulates genes/pathways directly linked to allergic response, epigenetic regulation of “master” transcription factors (such as NFkB) indirectly controls a wider range of downstream immune and in?ammatory responses 53,54 In addition to histone modi?cations and DNA methylation, other gene regulatory networks contribute to the control of gene expression, including microRNAs (miRNAs), small interfering RNAs (siRNAs), and long non-coding RNAs (ncRNA) 55 Cardiovascular diseases and epigenetics: Cardiovascular diseases, like atherosclerosis and heart disease, are major public health issues and leading causes of mortality within the world. Several risk factors for the disease, e.g. smoking, hyperlipidemia, and high blood pressure, have been identified, however the mechanism of the disease development remains processed 56-60. Epigenetic modifications in cardiovascular system identified the crucial role within the pathogenesis of cardiovascular disease 61. Epigenetic modification will directly or indirectly influence vascular cell growth, migration, and apoptosis.

Some microorganisms like bacterial and viral infections frequently cause epigenetic alterations in host cells 62-65. fig 12 The principal scheme regarding epigenetic regulations in heart failure development. Abbreviations: ?-MHC, the alpha-myosin heavy chain gene, SPR-Ca2 + ATPase, sarcoplasmic reticulum Ca2 + ATPase genes 1.12 Epigenetics of Endometriosis Endometriosis, de?ned as the presence and growth of functional endometrial-like tissues outside the uterine cavity, it is a common and benign gynecological disorder with a poorly understood and enigmatic etiopathogenesis and pathophysiology 66. It is cause of disability in women of reproductive age, responsible for dysmenorrhea, pelvic pain, and subfertility 67, it also impacts negatively on patients’ physical, mental, relational, and social wellbeing 68. In the United States, endometriosis is the third leading cause of gynecologic hospitalization 69,70.

1.13 Stem cell epigenetics in human disease Several recent lines of evidence underscore that stem cell differentiation and early mammalian development largely depend on the elasticity of epigenetic alterations 71. The mechanism of gene regulation during early development does not only rely upon the interactions among different transcription factors and signaling pathways, but also on epigenetic modi?cations, such as the ATP-dependent chromatin remodeling 72, covalent alterations of histones 73, exchange of histones and histone variant 74, DNA methylation at CpG islands 75, RNA-mediated gene regulation including RNAi pathways and non-protein-coding RNAs (ncRNA) 76,77. All of these have been found to play critical roles in maintenance of stem cell pluripotency/multipotency, blocking differentiation in stem cells, and controlling the inherited characteristics of cellular memories during early development. 1.14 Epigenetics of aging and age related disease Ageing,defined as the progressive functional decline of organisms at cellular, molecular, and physiological level, which is the main risk factor for major human diseases such as cancer, cardiovascular diseases or neurological disorders 78.Both increases and decreases in DNA methylation are associated with the aging process, and evidence is that age-dependent methylation changes are involved in the development of neurologic disorders, autoimmunity and cancer in elderly people.79 Methylation changes that occur in an age-related manner may include the inactivation of cancer related genes. In some tissues, levels of methylated cytosines decrease in aging cells, and this demethylation may promote chromosomal instability and rearrangements, which increases the risk of neoplasia.79 In other casses, such as the intestinal crypts, increased global hypermethylation may be the predisposing event that increased risk of colon cancer with advancing age.80 fig 13 Epigenetics and Human Infectious Diseases Patho-epigenetics is a new thinks that dealing with the pathological consequences of dys regulated epigenetic processes 81.

In which epigenetic alterations, induced by certain pathogenic viruses and bacteria in the host cells they are interacting with, and play an unexpected but most important role in disease initiation and progression. Pathogens, including protozoan parasites and fungi, that are use their own sophisticated epigenetic mechanisms to control the expression of their genomes 82-86.Oncogenic human adenoviruses that induce malignant tumors in experimental animals and elicit spectacular epigenetic alterations in tissue culture 87,88, but lack any association with human neoplasms. The epigenetic aspects of Helicobacter pylori infection were also analyzed most intensively, due to its association with gastric carcinoma. Regarding viruses infecting humans, the epigenotypes of tumor associated DNA viruses and pro viral DNA copies of retroviral genomes were characterized. Epigenetic studies may also contribute diseases caused by infectious pathogens, ?rst of all microbes, but also macro parasites, including helminths, fungi, and arthropods.

Epigenetic Therapy One main approach in epigenetic therapy is the reactivation of genes that have been silenced due to epigenetic modifications. Several drugs are used that aimed at inhibiting DNA methylation have been designed which include 5-azacytidine,5-aza-2′-deoxycytidine,etc.These drugs are mistaken for cytosine residues and thus get incorporated into DNA during replication. After incorporation into DNA, these drugs are ready to block DNMT enzymes thus inhibiting DNA methylation.Many others drugs also aimed at histone modification have also been designed and are referred to as histone deacetylase (HDAC) inhibitors. The function of HDAC is to remove acetyl groups from DNA, which condenses chromatine and thereby stops transcription. Inhibition of this process using HDAC inhibitors are phenylbutyric acid,SAHA, depsipeptide and valproic acd.89 Epigenetic process and changes are so widespread, which require craeful handling and caution.

Non-selective activation of gene transcritpion in normal cells could make theme cancerous, where the treatments could cause the very disorders they are trying to counteract. Thus, successful epigenetic treatment require selectivity towards abnormal cells. In the face of this possible drawback, epigenetic therapy is finding way to specifically target abnormal cells with minimal damage to normal cells. CONCLUSION Epigenetic processes not only take many forms, but they also can readily become expressed as human diseases. These diseases, that can be loosely grouped under the heading of “epigenetic diseases”, are vast and the list of diseases that ?t into this description is rapidly growing. Elucidation of the epigenetic aberrations in human diseases not only has implications for epigenetic-based therapy, but also for risk assessment, prevention, progression analysis, prognosis and biomarker development.

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