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Epigenetics of Human Disease
Trygve O. Tollefsbola,b,c,d,e*
a Department of Biology, University of Alabama at Birmingham, AL 35294
b Center for Aging, University of Alabama at Birmingham, AL 35294
c Comprehensive Cancer Center, University of Alabama at Birmingham, AL 35294
d Nutrition Obesity Research Center, University of Alabama at Birmingham, AL 35294
e Comprehensive Diabetes Center, University of Alabama at Birmingham, AL 35294
*Corresponding Author:
Department of Biology, 175 Campbell Hall
1300 University Boulevard
Birmingham, AL 35294-1170, USA
Tel: +1-205-934-4573
Fax: +1-205-975-6097
E-mail: trygve@uab.edu
Running Title: Epigenetics of Human Disease
Abstract
It is now apparent that DNA information inherent in its sequence is not the only or even the prevailing factor in the molecular biology of disease. Rather, epigenetic factors not involving DNA sequence often have a major impact on disease development. The predominant epigenetic mechanisms consisting of DNA methylation, chromatin modifications and non-coding RNA have vast and long-term effects on health and aberrations in these processes can often contribute to disease. However, numerous advances in epigenetic-based disease prevention and therapy are on the horizon and could revolutionize medicine and clinical practice.
Keywords: Epigenetic, human, disease, DNA methylation, histone modification, non-coding RNA
Introduction
Epigenetics does not involve changes in DNA sequence but is nevertheless able to influence heritable gene expression through a number of processes such as DNA methylation, modifications of chromatin and non-coding RNA. Aberrations in DNA methylation are common contributors to disease. For example, imprinting diseases such as the Angelman, Silver-Russell, Prader-Willi and Beckwith-Wiedeman syndromes are often associated with alterations in DNA methylation [1]. Human diseases attributable to DNA methylation-based imprinting disorders, however, have not been limited to these genetic diseases as diabetes, schizophrenia, autism and cancer have also been associated with aberrations in imprinting. Abnormalities of the enzymes that mediate DNA methylation can also contribute to disease as illustrated by the rare Immunodeficiency-Centromere instability-Facial anomalies (ICF) syndrome caused by mutations in DNA methyltransferases 3B (DNMT3B). Likewise, Rett syndrome, related to mutations in the methyl-binding domain (MBD) protein, MeCP2, leads to dysregulations in gene expression and neurodevelopmental disease [2]. Perhaps most commonly, DNA methylation aberrations 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.
Histone modifications frequently contribute to disease development and progressions and histone acetylation or deacetylation are the most common histone modifications involved in diseases. Aberrations in histone modifications can significantly disrupt gene regulation, a common factor in disease, and could potentially be transmissible across generations [3]. Histone modifications have in fact been associated with a number of diseases such as cancer and neurological disorders. Collaborations between DNA methylation and histone modifications can occur and either or both of these epigenetic processes may lead to disease development [4].
Non-coding RNAs are 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 3’ end of the mRNA and prohibit the actions of transfer RNA [5]. Although miRNAs have been associated with a number of diseases such as Crohn’s disease [6], their role in tumorigenesis is now established and is considered to be a frequent epigenetic aberration in cancer.
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 variation methods
Technological advances often serve as a major stimulus for knowledge development and the field of epigenetics is no exception in this regard. Recent advances in epigenetic-based methods have served as major driving forces in the fascinating and ever-expanding epigenetic phenomena that have been revealed especially over the past decade. Although genome-wide maps have been developed, there is still a need for maps of the human methylome and histone modifications in healthy and diseased tissues as discussed in Chapter 2. Epigenetic variation is especially prominent in human diseases and established techniques such as bisulfite genomic methylation sequencing and chromatin immumoprecipitation (ChIP) analyses are revealing numerous epigenetic aberrations involved in disease processes. However, cutting-edge advances in comparative genomic hybridization (CGH) and microarray analyses as well quantitative analysis of methylated alleles (QAMA) and many other developing technologies are now facilitating the elucidation of epigenetic alterations in disease that were previously unimagined. Combinations of epigenetic technologies are also emerging that show promise in leading to new advances in understanding the epigenetics of disease.
Cancer epigenetics
As aforementioned, DNA methylation is often an important factor in cancer development and progression. DNA methylation changes can now be readily assessed from body fluids and applied to cancer diagnosis as well as the prognosis of cancer (Chapter 3). Epigenome reference maps will likely have an impact on our understanding of many different diseases and may lead the way to breakthroughs in the diagnosis, prevention and therapy of human cancers. Histone modifications are frequently altered in many human cancers and the development of a histone modification signature may be developed that will aid in the prognosis and treatment of cancers (Chapter 4). These histone maps may also have potential in guiding therapy of human cancers. MicroRNAs (miRNAs) are central to many cellular functions and they are frequently dysregulated during oncogenesis (Chapter 5). In fact, miRNA expression profiles may be more useful than gene expression profiles for clinical applications since there are fewer mRNA regulatory molecules. These miRNA profiles may be applicable to identifying various cancers or to stratify tumors in addition to serving prognostic or therapeutic roles. Epigenetic therapy for cancer is perhaps one of the most exciting and rapidly developing areas of epigenetics. As discussed in Chapter 6, approaches are available for targeting enzymes such as the DNMTs, histone acetyltransferases (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs) and histone demethylases (HDMTs). The development of drug-based inhibitors of these epigenetic-modifying enzymes could be further improved through drug combinations or even natural plant-based products, many of which have been found to harbor properties that can mimic the often more toxic and perhaps less bioavailable epigenetic drugs that are currently in use.
Epigenetics of neurological disease
One of the newer areas of epigenetics that has been rapidly expanding is its role in neurological disorders or disease. These disorders are not limited to the brain as the disease target, but also often involve nutritional and metabolic factors that contribute as well to conditions such as neurobehavioral diseases (Chapter 7). At this point, however, the number of neurodevelopmental disorders that have been associated with epigenetic aberrations is not very extensive. A possible explanation for this is that the pervasive nature of epigenetic processes could serve as a negative selective force against more localized disease such as neurodevelopmental disorders (Chapter 8). In fact, many neurodevelopmental disorders are due to partial loss-of-function mutations or are X-chromosomal mosaics with recessive X-linked mutations. Neurodegenerative diseases such as Alzheimer’s disease have been increasingly associated with alternations in epigenetic processes. Environmental factors such as diet and exposure to heavy metals may lead to the epigenetic changes often involved in Alzheimer’s disease eventually contributing to increased amyloid peptide (Chapter 9). These factors may begin early in life and manifest as late-onset forms of Alzheimer’s disease. Fortunately, as reviewed in Chapter 10, a number of new approaches are currently being developed that could have translational potential in preventing or treating many of the epigenetic changes that are being revealed as an important component of neurobiological disorders.
Autoimmunity and epigenetics
There is a strong association between environmental factors, age and the development of autoimmune disorders. Epigenetic processes are central to aging and are also an important mediator between the environment and disease and it is thought that these factors may be important in the development and progression of numerous autoimmune diseases. For example, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune disorders that have frequently been associated with aberrations in epigenetic mechanisms (Chapter 11). Often the epigenomic and sequence-specific DNA methylation changes found in SLE and RA affect key genes in immune function. Two challenges are to increase the use of high-throughput approaches to these diseases to mine for additional gene aberrations and to translate these epigenetic changes to the clinic through the development of novel approaches for preventing or treating SLE and RA. Fortunately, there is hope for epigenetic therapy of autoimmune disorders as reviewed in Chapter 12. Much of the current research for drug-development relevant to autoimmune dysfunction is focused on correcting alterations in DNA methylation and histone acetylation. However, recent exciting advances suggest promising avenues for drug development as applied to miRNAs. For instance, miRNAs or inhibitors of miRNA to impact DNA methylation may have utility in affecting gene transcription in immune cells that often lead to the development of SLE.
Human imprinting disorders
Both DNA methylation and histone modifications can impact imprinting centers that control parent-of-origin specific expression and lead to human imprinting disorders. These disorders, such as Angelman, Prader-Willi, Silver-Russell and Beckwith-Wiedeman syndromes frequently involve epigenetic changes that contribute to these disorders and they often manifest at a very young age (Chapter 13). However, both epigenetic and genetic factors are often important in human imprinting disorders and the development of epigenetic therapy approaches in this particular area represents a considerable challenge. Advances are being made in understanding the epigenetic basis of human imprinting disorders which may provide breakthroughs in treating these tragic diseases.
Epigenetics of obesity
Rare obesity-associated imprinting disorders have been described and dietary modulation efforts have suggested an epigenetic component may exist in these disorders. In fact, the major role of environmental factors in obesity strongly suggests a role of epigenetic changes such as those involving DNA methylation in obesity (Chapter 14). Early-life environmental factors could be especially important in controlling epigenetic aberrations that may contribute to obesity as reviewed in Chapter 15. It is likely that increased identification of obesity biomarkers and their associated epigenetic factors may lead to new advances in controlling the extant epidemic in childhood obesity in many developed countries. It is highly likely that nutritional or lifestyle interventions either during pregnancy or early in life could impact processes such as DNA methylation and histone modifications that are highly responsive to environmental stimuli and lead to means to control obesity at very early ages.
Diabetes: The epigenetic connection
Similar to obesity, environmental factors are also often important in the development of type 2 diabetes. Non-genetic risk factors such as aging and a sedentary lifestyle have been associated with epigenetic aberrations characteristic of type 2 diabetes (Chapter 16). Since markers such as DNA methylation have been shown to vary in diabetic versus non-diabetic individuals, it is very possible that epigenetic manifestations may have a key role in the pathogenesis of type 2 diabetes. However, multi-system studies are currently needed to further substantiate this concept and additional studies on the prediction and prevention of type 2 diabetes are sorely needed. Histone modifications have also been strongly implicated in diabetes as reviewed in Chapter 17. In fact, HDAC inhibitors may have potential in treating diabetes in the short-term. Nutritional compounds that lead to HDAC inhibition may have potential in treating type 2 diabetes as well as the development of miRNA-based therapeutics that would have greater targeting potential.
Epigenetics and allergic disorders
Consistent with many other epigenetic diseases, early environmental factors appear to be a critical component to the development of numerous allergic disorders. For example, exposure to specific factors in utero may be associated with epigenetic aberrations that affect gene expression, immune programming and the development of allergic maladies in the offspring (Chapter 18). Additionally, this transgenerational component may allow for the transmittance of epigenetic changes to future generations beyond the offspring leading to allergic disorders. Novel early interventions into epigenetic-modifying factors such as maternal diet may contribute to an eventual decline in allergy-based disorders. Asthma is a common disorder of this nature and there is some evidence that corticosteroids exert their anti-inflammatory effects in part by inducing acetylation of anti-inflammatory genes (Chapter 19). The potential recruitment of HDAC2 to activated inflammatory genes by corticosteroids may be a key mechanism for epigenetic-based therapy of allergic disorders such as asthma. Future efforts are now being directed toward modifiers of other epigenetic processes in allergic disorders such as histone phosphorylation and ubiquitination.
Cardiovascular disease and epigenetics
Atherosclerosis is a major precipitating factor in cardiovascular diseases and the functions of smooth muscle cells (SMCs) and endothelial cells (ECs) are central to the development of atherosclerosis. Mounting evidence has indicated that epigenetic processes such as DNA methylation and histone acetylation have critical functions in modulating SMC and EC homeostasis. The SMC and EC proliferation, migration, apoptosis and differentiation not only contribute to atherosclerosis, but also cardiomyocyte hypertrophy and heart failure as reviewed in Chapter 20. The role of HDACs in cardiovascular disease such as arteriosclerosis has been showing promise although concerns surround the tissue-specificity of these agents. Given this concern, the development of highly selective and cell type-specific HDAC inhibitors may have potential in epigenetic-based therapies for cardiovascular diseases of varied types.
Epigenetics of human infectious diseases
A common theme is the environmental impact on the epigenome and its role in epigenetic disease processes. Consistent with this concept, bacterial and viral infections often cause epigenetic changes in host cells that lead to pathology as reviewed in Chapter 21. The consequences of these epigenome-modifying infections are not limited to neoplasia. There are, in fact, many other diseases that have an epigenetic basis induced by infectious agents such as diseases of the oral cavity. Even organisms like protozoa can contribute to host epigenetic dysregulation. Knowledge accumulated regarding epigenetic “invaders” of the genome and their pathological consequences will undoubtedly lead to the development of more sophisticated and novel approaches to controlling and treating epigenetic-based infectious diseases.
Reproductive disorders and epigenetic aberrations
Endometriosis, or the presence of functional endometrial-like tissues outside of the uterine cavity, is often secondary to hormonal and immunological aberrations. Most exciting in the context of epigenetics, however, is that many recent studies have indicated that endometriosis may have an important epigenetic component that contributes to its pathological progression (Chapter 22). A number of investigations have indicated HDAC inhibitors may be effective in treating endometriosis. There is also potential for the development of epigenetic biomarkers for endometriosis such as changes in DNA methylation as well as miRNA-based biomarkers. Epigenetic processes are also gaining increasing importance in endometrial cancer (Chapter 23). Damage to the mismatch repair system appears to play a significant role in the development of endometrial cancer through the mechanism of hMLH1 hypermethylation. These findings may have important epigenetic therapeutic implications for endometrial cancer and could also have potential for the prevention, diagnosis and risk assessment of endometrial cancer.
Stem cell epigenetics in human disease
Stem cell-based therapeutic approaches could lead to powerful means of treating human diseases and epigenetic regulatory signals play an important role in the maintenance of stem cell potency (Chapter 24). Chromatin modifications and dynamics appear to have an important role in conservation of pluripotency and the differentiation of embryonic stem cells which are central factors in stem cell-based therapeutics. In fact, several epigenetic disorders have been modeled in vitro through the use of induced pluripotent stem cells (iPSCs) from the cells of patients. Understanding the basic epigenetic changes central to these processes may have considerable potential in the treatment of human epigenetic diseases. Non-coding RNAs also participate in stem cell renewal and differentiation (Chapter 25). The role of epigenetics and non-coding RNAs may provide many useful tools for manipulating stem cell programming as applied to therapy of epigenetic-based diseases.
Epigenetics of aging and age-associated diseases
Few processes are as pervasive as aging which impacts not only the entire physiological fitness of an organism, but also its predisposition to developing age-related diseases which is comprised of an ever-growing list of diseases. It is now apparent that epigenetic processes are major components of aging which opens many avenues to human diseases (Chapter 26). Although aging is not considered a disease in and of itself, it is perhaps the most frequent contributor to human disease. Therefore, delaying the epigenetic aberrations associated with aging through epigenetic intervention and treating epigenetic-based age-associated diseases could have a tremendous impact on the role of epigenetics in human disease. Although they are on opposite sides of the lifespan spectrum, early developmental processes are likely linked to later life aging and age-associated diseases (Chapter 27). The role of nutrition hormones and metabolic environment early in life can have effects throughout life, influence epigenetic pathways and markers and manifest in the form of aging and age-related diseases. Considerable interest is now focused on the impact of early life epigenetic impacts and the outcome of these effects on the myriad of age-associated diseases which comprise much of the pathology that forms the basis of human disease.
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 fit 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. A common theme of many epigenetic-based human diseases is the role of the environment. This may take varied forms ranging from maternal nutrition to infectious agents. Exciting advances are rapidly developing that are contributing significantly toward the management of human diseases through epigenetic intervention. It is anticipated that epigenetic-based preventive and therapeutic strategies will continue to develop at a rapid pace and may assume a role at the forefront of medicine in the not too distant future.
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