PUBLISHED IN ISSUE 2 | FALL 2022
Epigenetics
Kaylee Gleason
Emporia State University
Epigenetics can be defined as chemical modifications of DNA that affect gene expression without altering nucleotide sequence. These modifications are considered stable and can be passed onto descendent cells and progeny. The three main epigenetic modifications are DNA methylation, post-translational chromatin modifications, and the actions of noncoding RNAs that will either enhance or suppress gene expression. Current research includes the association of epigenetic modifications in cancer and potential inhibitors of DNA methyltransferases (DNMTs) in cancer treatments. The ethical dilemmas of epigenetics, such as intergeneration equity and confidentiality, are important and warrant reflection considering the many future implications of epigenetic research. The field of epigenetics is full of promise as it potentially encompasses the complex answer to how and why humans age through the analysis of the epigenetic clock hypothesis. Epigenetic research is rapidly expanding as substantial progress has already been made in the International Human Epigenome Consortium (IHEC) project which seeks to produce reference maps of human epigenomes for key cellular states relevant to human health and disease. The field of epigenetics is important in understanding the pathophysiology of human disease and will potentially change the way healthcare professionals practice medicine.
Epigenetics is a rapidly evolving field in science and research, encompassing a wide range of investigative areas including genetics, genomics, molecular biology, and medicine. The mechanics of epigenetics is essential in development, homeostasis, as well as in many human pathologies (Oppermann, 2013). DNA methylation, post-translational chromatin modifications, and noncoding RNA action all serve integral roles in gene regulation, imprinting, and silencing. Through the targeting of epigenetics, therapeutic intervention of many disorders is possible and will change the way healthcare professionals practice medicine. In this article, a brief history on the field of epigenetics will be reviewed as well as the epigenetic mechanisms. Current epigenetic research, potential ethical dilemmas in the field, and exciting developments in epigenetics will also be discussed. An appreciation of the essential role that epigenetics serves in many human diseases will also be acquired.
INTRODUCTION
ABSTRACT
EPIGENETICS-WHAT IS IT?
Epigenetics is the phenomenon of chemical alterations occurring in DNA that do not alter nucleotide sequence. These alterations can be any modification of chromatin or DNA structure that affects gene expression. Epigenetic modifications are often stable and can be passed onto descendant cells and individuals through mitosis and meiosis. Throughout the process of development, epigenetics influences how a genotype expresses a certain phenotype. Epigenetics help define phenotypes and explain the phenotypic differences observed between monozygotic twins (Loscalzo and Handy, 2014).
EPIGENETICS-DISCOVERY
The history of epigenetics is linked with the study of evolution and development. Aristotle first spoke about a gradual development from an undifferentiated origin, which he called “epigenesis,” to support his opposition of preformation (Ganesan, 2018). About 2000 years later, Conrad Waddington resurrected this idea and coined the name “epigenetics.” In Waddington’s paper, The Epigenotype, he described epigenetics as the relationship between genotype and phenotype as well as the complex of developmental processes (Waddington, 1942). Riggs and Porter contributed to the working definition of epigenetics by recognizing that the phenomenon is comprised of heritable changes in gene function that do not alter DNA sequence. In 2009, the definition of epigenetics was yet again expanded to include the idea that the initiation of the new epigenetic state should involve a transient mechanism different from the one required to maintain it (Felsenfeld, 2014).
EPIGENETICS-MECHANISM
Exogenous factors and environmental exposures affect epigenetic modifications by providing a mechanistic link between the environment and the genome (Loscalzo and Handy, 2014). To understand the mechanism of epigenetics it is first important to review how DNA is organized. Nuclear DNA associates with specific nuclear proteins into chromatin. The DNA then forms nucleosomes by coiling around positively charged histone proteins. The nucleosome is composed of an octameric core of histone proteins (two H3-H4 histone dimers and two H2A-H2B dimers) bound to a 147 base-pair strand of DNA (Loscalzo and Handy, 2014). The structure of the chromatin is determined by nucleosome spacing and is classified as either heterochromatin or euchromatin. Heterochromatin is densely packed and transcriptionally inactive while euchromatin is not packed as densely which allows for transcription to occur. Chromatin’s structure, and in turn its consequences on gene expression, are regulated by chemical modifications to the amino-terminal histone tails that extend from the nucleosome as well as modifications to the DNA itself without altering nucleotide sequence (Song et al., 2011).
Epigenetic modifications can be brought about by DNA methylation, posttranslational modification of histone proteins, or noncoding RNA action in the nucleus (Loscalzo and Handy, 2014). In DNA methylation, a methyl group is covalently attached to the 5th carbon of cytosine and is the principle epigenetic modification of DNA. DNA methylation occurs primarily in CpG dinucleotide regions, most notably in regulatory sequences that suppress gene expression. Methylation of cytosines not found in CpG sequences can also occur, which is important for the regulation of gene expression in embryonic stem cells. This covalent modification is also important for the transcriptional repression of transposons and repeat elements as well as in imprinting and X-chromosome inactivation. Methylation also plays a role in tissue-restricted gene expression during development and differentiation (Loscalzo and Handy, 2014). DNA methylation represses transcription by inhibiting the binding of transcription factors or by promoting the binding of transcriptional repressors such as histone deacetylases (HDACs).
The methylation of cytosine at CpG dinucleotides is accomplished through a family of enzymes known as the DNA methyltransferases (DNMTs). This family of enzymes include de novo methyltransferase DNMT3a, DNMT3b, and DNMT1; during DNA replication, DNMT1 will recognize and methylate the nonmethylated daughter strand. Reciprocal methylation during subsequent cycles of DNA replication is permissive due to the base-pairing rules and offers a mechanism for the inheritance of a non-genetic trait to daughter cells. Due to this phenomenon, DNA methylation is considered a long-term, stable epigenetic trait (Loscalzo and Handy, 2014).
Posttranslational modifications of histones include acetylation, methylation, phosphorylation, and ubiquitination. These chemical modifications result in changes of chromatin structure which ultimately affects gene expression. According to the Histone Code hypothesis, different types and combinations of modifications will lead to different transcription potentials (Loscalzo and Handy, 2014). Acetylation of the ε-amino group of lysine in the amino-terminal tails of histones H3 and H4 have been shown to consistently promotes transcription. Transcriptional cofactors, cyclic-AMP response element-binding protein and p300 recruit histone acetyl transferases to add acetyl groups to the amino-terminal tails of histone proteins. The deacetylation of histones is associated with CpG methylation and inactive chromatin structure. The HDACs that facilitate deacetylation are also regulated by posttranslational modifications (Loscalzo and Handy, 2014).
The methylation of histone lysine is another noteworthy class of histone modification that affect gene expression. Whether gene expression is repressed or promoted, depends on the position of the lysine and the extent of its methylation. Just as histone acetylation is easily reversed, histone methylation is also reversible by the action of histone lysine methyltransferases and demethylases that target specific mono-, di-, or trimethylation states of lysine (Loscalzo and Handy, 2014).
Long noncoding RNAs are important in imprinting and in X-chromosome inactivation. These long noncoding RNAs can recruit remodeling complexes, such as the polycomb complex, to silence genes by promoting histone methylation (Loscalzo and Handy, 2014). RNA-binding proteins can also be recruited to impair histone deacetylation or to inhibit transcription factors from binding to promoter regions. Short, noncoding RNAs such as small inhibitory RNAs and dicer-dependent microRNAs play roles in the suppression of transcription through the recruitment of specific argonaute proteins. Arognaute proteins will form epigenetic remodeling complexes that promote histone deacetylation, histone methylation, and DNA methylation. The transgenerational inheritance of RNA-induced epigenetic silencing is accomplished through protein interaction world-interacting RNAs (Loscalzo and Handy, 2014).
CURRENT EPIGENETICS RESEARCH
Cancer epigenetics encompasses a wide range of heritable changes in gene expression, unrelated to alteration in DNA sequences that contribute to the development of cancer. DNA methylation, histone modifications, and the expression of long noncoding RNAs are the epigenetic mechanism associated with tumor initiation, cancer progression, and metastasis (Cecotka and Polanska, 2018). Within the past decade, cancer epigenetics has led to the development of novel biomarkers and therapeutic targets for many types of cancer.
Traditional cancer genetic studies focus on abnormal gene expression brought about by mutations; epigenetics cancer research fixates on the regulation of gene expression without altering the genomic sequence. Aberrant DNA methylation patterns including hyper- and hypo-methylation have been reported in different types of cancer. Hypermethylation of specific genes explains the role of DNMTs in tumorigenesis. The hypermethylation of CpG islands in TSG promoters, such as Braca1, Rb, or p53 promoters, results in the inactivation of each gene and can enhance cancer development (Barbano et al., 2012).
Targeting the epigenetics of cancer by focusing on aberrant DNA methylation patterns has shown much promise in current research on cancer and epigenetics. Two cytidine analogs, 5-azacytidine/vidaza (AZA) and 5-aza-2’-deoxycytidine/dacogen (DAC), have been approved by the FDA as treatments of myelodysplastic syndromes (Kantargin et al. 2012). AZA and DAC form an irreversible covalent complex with DNMT1 and causes proteasome mediated DNMT1 degradation. Currently, second-generation analog, guadecitabine (SGI-110), is being tested in clinical trials for MDS and acute myeloid leukemia (Kantargin et al. 2012).
Due to the reversible nature of epigenetic modifications, it has been suggested that DNA hypermethylation at promoter CGIs could be reversed to achieve a re-expression of silenced genes and in this way, reprogram cancer cells to a normal state (Spencer et al., 2017). The study of DNMT inhibitors for the treatment of cancer has exhibited much progress with the two compounds, decitabine and azacitidine. These two drugs have shown significant success with repeated exposure at low doses in clinical trials. These inhibitors work by integrating into newly synthesized DNA where they form a covalent bond with DNMTs. This leads to the degradation of DNMTs and the hypomethylation of the genome. Decitabine incorporates itself into DNA, while azacitidine can incorporate itself into both DNA and RNA (Spencer et al., 2017).
In addition to the, ground-breaking research involving epigenetics and cancer, there are many other current studies regarding epigenetics. A few of the most notable studies involving epigenetics include the association of the pathophysiology of depression with epigenetics, plant epigenetics, and epigenetic trends in cardiovascular disease.
ETHICAL DILEMMAS OF EPIGENETICS
Although, epigenetics research shows much promise in the treatment of many human diseases, there are many ethical dilemmas to be aware of in the face of this great scientific discovery. One potential ethical dilemma is the issue of intergenerational effects and the equity of epigenetics research (Rothstein et al., 2011). An important factor of epigenetics research is the study of the epigenome when an induvial is exposed to environmental and sometimes hazardous exposures. This not only affects the gene expression of the exposed individual but also can affect the individual’s progeny and subsequent generations. New challenges arise such as intergeneration equity. Intergeneration equity is the obligation of each generation to serve as a “steward” of the planet and its future inhabitants. According to this rationale, it could be asserted that each generation has an obligation to its descendants to not damage the epigenomes of subsequent generations through exposure to environmental hazards (Rothstein et al., 2011).
Epigenetics research can also unveil a substantial amount of important healthcare information. Potential information that can be revealed by the analysis of an epigenome include the probability that an individual will develop certain health problems and the likelihood they could transmit this risk onto their children. This raises the concern of privacy and confidentiality through unauthorized or compelled disclosures. The current, “State Genetic Privacy Laws,” of the United States do not include the protection of epigenetic data, so new privacy legislation may be necessary to protect sensitive, epigenetic information (Rothstein et al., 2011).
MISCELLANEOUS FACTS
Epigenetics has been found to play key roles in many diseases, as well as in development and cell differentiation. Interestingly, epigenetics also has the potential to serve as a predictor of ageing. This is known as the epigenetic clock, and it may be able to use DNA methylation age as a clinical biomarker. Common clinic biomarkers that accurately predict the risk of age-related diseases and mortality include cellular senescence, genomic instability, telomere attrition and mitochondrial dysfunction. It has been shown that changes in DNA methylation patterns occur with age and may be a fundamental mechanism that drives human ageing (Slieker et al., 2016).
In January of 2010, the International Human Epigenome Consortium (IHEC) was formed. The IHEC is currently working to coordinate the production of reference maps of human epigenomes for key cellular states relevant to human health and disease. In this exciting project, new ways to monitor and/or manipulate the epigenome are being investigated as well as the examination of epigenetic features associated with disease and, in turn, implementing these discoveries to improve human health. As of 2016, the IHEC has generated over 7000 datasets available to the public to improve the utility of epigenome data for biological and medical application (Stunnenberg, 2016).
IMPLICATIONS FOR TODAY
As observed with Carver and Wiman, writing can help people deal with their uncertainty and confusion, highlighting its role in emotional healing. Alan Lenhoff, editor of the Medical Laboratory Observer, emphasizes how poetry can serve as emotional and medical education support. While admitting that poetry might not offer responses to people dealing with disease, Lenhoff holds that poems transmit beauty and truth, helping people cope with challenges (4). Not only can poetry help patients, but poems can also convey perspectives that readers had not considered before. To illustrate his point, Lenhoff provides the example of Dr. Rafael Campo. Dr. Campo is a professor at Harvard Medical School who incorporates the analysis of poetry in his classes, recognizing the importance of “treating the whole patient, and that includes the emotional component of facing serious illness” (Lenhoff 4). As more studies about this subject are conducted, there will be more awareness about the critical connection between writing and emotional health and its effect on physical well-being.
Organizations also recognize the therapeutic potential of poems. For instance, the Hippocrates Initiative for Poetry and Medicine endorses the value of poetry as emotional support by conducting annual poetry contests about medicine (Lenhoff 4). Similarly, in her article “Why We Need More Poetry in Palliative Care,” Dr. Elizabeth Davies from King’s College shares and encourages participation in initiatives that utilize poetry to foster healing in hospitals. Some of these initiatives include “Poems in the Waiting Room,” where clinics in England and New Zealand distribute cards with poems, and the allocation of postcards with poems by the nurses at The Aberdeen Royal Infirmary (Davies 268). These initiatives are essential as they encourage patients and medical workers to reflect on their experiences. Given its benefits, reading poems from authors who have fought disease can promote empathy among medical workers and help patients realize that they are not alone in their battle.
Many patients and physicians have found poetry helpful during their battle against disease. Kaichiro Tamba, an assistant professor at Jichi Medical School, describes how he prepared personalized haikus for his patients and family members to help them grieve and heal. In each medical case, Tamba explains how his relationship with the patient and relatives became significantly closer after sharing poems. For example, Tamba wrote a haiku for a patient battling lymphoedema in his legs, and in the poem, he included the patient’s name, last name, and beloved restaurant (534). Tamba notes how the patient was “very pleased, understanding how much I thought of him. Although pain control was difficult, he was pleased to see me each time I visited” (535). This account demonstrates that poetry can indeed comfort patients and strengthen patient-physician relationships.
It is also possible that poetry in palliative care has some limitations in its healing role. This case might apply to patients with cognitive disabilities or dementia. However, it is crucial to remember that these poems not only provide serenity for patients but also for relatives and healthcare workers. After getting a slightly better understanding of the patient’s perspective, medical professionals can treat the patient with cognitive disabilities more empathetically. Similarly, family members can reach healing for their loss through reflective writing. When there are language differences between patient and physician, poetry can still positively impact their interactions with some accommodations. Even if the poems they read and the reflections they write are in different languages, both patient and physician can benefit from the healing potential of literature. Day after day, poetry proves the immense power of words in helping humanity to heal physically and emotionally. Consequently, reading and writing poetry should be a more frequent practice in the medical field as it addresses the often-overlooked emotional and humane aspect of this discipline.
LITERATURE CITED
Barbano, R., Muscarella, L., et al. (2012). Aberrant Keap1 methylation in breast cancer and association with clinicopathological features. Epigenetics, 8(1), 105-112. https://doi.org/10.4161/epi.23319
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Cecotka, A., Polanska, J. (2018). Region-Specific Methylation Profiling in Acute Myeloid Leukemia. Interdisciplinary Sciences: Computational Life Sciences, 10(1), 33-42. https://doi.org/10.1007/s12539-018-0285-4
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Felsenfeld, G. (2014). A Brief History of Epigenetics. Cold Spring Harbor Perspectives in Biology, 6(1). https://doi.org/content/6/1/a018200.full
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Ganesan, A. (2018). Epigenetics: the first 25 centuries. The Royal Society Publishing, 373 (1748). https://doi.org/10.1098/rstb.2017.0067
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Kantarjian, H., Thomas, X., et al. (2012). Multicenter, Randomized, Open-Label, Phase III Trial of Decitabine Versus Patient Choice, with Physician Advice, of either Supportive Care or Low-Dose Cytarabine for the Treatment of Older Patients with Newly Diagnosed Acute Myeloid Leukemia. Journal of Clinical Oncology, 30(21), 2670-2677. 10.1200/JCO.2011.38.9429
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Loscalzo, J., Handy, D. (2014). Epigenetic Modifications: Basic Mechanisms and Role in Cardiovascular Disease. Pulmonary Circulation, 4(2), 169-174. https://doi.org/10.1086/675979
Oppermann, U. (2013). Why is epigenetics important in understanding the pathogenesis of inflammatory musculoskeletal diseases?. Arthritis Research Therapy, 15(209). https://doi.org/10.1186/ar4186
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Rothstein, M., Cair, Y., et al., (2011). Ethical Implications of Epigenetics Research. Nature Reviews Genetics, 10(4), 224-224. https://dx.doi.org/10.1038%2Fnrg2562
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Slieker, R., Iterson, M., et al. (2016). Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms. Genome Biology, 17(1), 1-13. https://doi.org/10.1186/s13059-016-1053-6
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Song, L., Zhang, Z., et al. (2011). Open Chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Research, 21(10), 1757-1767. https://dx.doi.org/10.1101%2Fgr.121541.111
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Spencer, D., Germain-Russler, D., et al. (2017). CpG Island Hypermethylation Mediated by DNMT3A Is a Consequence of AML Progression. The Cell, 168(5), 801-816. https://doi.org/10.1016/j.cell.2017.01.021
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Stunnenberg, H. (2016). The International Human Epigenome Consortium: A Blueprint for Scientific Collaboration and Discovery. The Cell, 167(5), 1145-1149. https://doi.org/10.1016/j.cell.2016.11.007
Waddington, C. H. (1942). The Epigenotype. International Journal of Epidemiology, 41(1), 10- 13.
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