Epigenetics: An Overview

May 5, 2023 | Written by Anurag Srivastava, PhD | Reviewed by Scott Sherr, MD and Marion Hall

Epigenetics: An Overview

For eternity, the biggest question in the mind of scientists is how a complex organism is formed with varied types of cells from a single fertilized egg. With the discovery of chromosomes and the establishment that DNA is the heredity material, scientists became curious to know how more than 100 cell types originate from a single DNA sequence in humans.

To answer these questions, scientists started investigating developmental biology with a genetics approach to understand the complex developmental processes. In 1942, Scottish embryologist Conrad Waddington coined the term “epigenetics” to explain the complex developmental process from genotype to phenotype.

Epigenetics in its modern form with molecular understanding has taken shape since the 1990s. Even the accepted standard definition of epigenetics, “stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence,” was framed at a Cold Spring Harbor meeting in 2008. 

In this article, we will look at the historical timeline of the evolution of epigenetics, the science behind it, the common epigenetic signatures, and finally, an overview of its role in clinical settings. 

Timeline of Epigenetics


The Lamarckian evolution theory, where Lamarck said that the environment gives rise to changes in animals. This was the first instance of epigenetics being discussed in the scientific community [1].


Discovery of chromosomes by Walther Flemming and their behavior in cell division [2].


Muller demonstrated sex-chromosome genetic linkage to many Drosophila genes [3].


Waddington coins the term “epigenetics” and defines it as the “implementation of cellular genetic programming for development [1]."


Discovery of Barr Bodies [1].


McClintock showed, for the first time, that transposable loci regulate the gene function, as transposition was the cause of phenotypic alterations in maize as a mosaic color [4].


Hannah showed, for the first time, the function of the heterochromatin and euchromatin region in a Drosophila chromosome [5].


Nanny proposed two regulatory systems in his landmark essay: “Epigenetic control systems [6]."


Ohno proved that the “sex chromatin,” a female-specific chromosome, was, in fact, an X chromosome, which gets inactivated during early embryonic development [1].


Discovery of lysine acetylation as a post-translational modification in histone [1].


Characterization of the structure of nucleosomes [7].


Holiday, Pugh, and Riggs showed that methylation of DNA nucleotides could at least partially account for Barr Body chromosomal inactivation [8,9].


Holiday proposed a “New Theory of Carcinogenesis,” where he said, “DNA damage by carcinogens could lead to loss of epigenetic information, specifically, that “replacement” DNA would lose any pre-existing methylation marks and, if in the right gene, might partially explain tumorigenesis [10].


Jones provided evidence that DNA methylation is behind the inactivation of the X chromosome in early female embryonic development [11].


The regulatory role of noncoding RNA (ncRNA) was shown in the landmark discovery by Ambrose and his colleague [12].


Discovery of RNA interference [13].


First time showed that the risk of lupus is increased with genetic mutations in the methylcytosine-binding protein 2 (MECP2) gene [14].


The standard definition of epigenetics was established.


It was demonstrated that overexpression of MECP2 altered all three epigenetic controls, namely DNA methylation, noncoding RNA, and histone post-translational modification.


Role of noncoding RNA in the inactivation of the X chromosome [1].


Horvath established the role of the epigenetic clock in aging [15].

The Science behind Epigenetics

The central dogma of molecular biology came with the discovery of DNA as genetic material. It stated that genetic information flows only in one direction, from DNA to RNA to protein. This has now been debunked as the role of the environment in modulating gene expression came to light.

Epigenetics plays a vital role in actively regulating gene expression by turning genes on or off. The new, more comprehensive approach requires understanding how an individual’s genetic information is affected by the interplay of exposomes, genetics, and epigenetics.

Types of Epigenetic Signatures

Gene expression is mainly regulated by its three major control signatures. For a more in-depth discussion of these and their clinical applications, we encourage you to check out the epigenetics module on homehope.org. But here is a quick overview: 

  1. DNA methylation: CpG dinucleotides (otherwise known as CpG islands or areas of thee genetic code with CGCG of >4=50%) are methylation's primary targets. In general, methylated genes are turned off and unmethylated genes are turned on, but this may not be the case, depending on where on the gene the CpG islands fall. DNA methylation levels are extremely high in the heterochromatic portions of the genome (centromeres, transposons, telomeres, and repetitive sequences). DNA methyltransferase (DNMT) acts as a mediator for DNA cytosine methylation. The irregular methylation pattern of DNA has been linked with many diseases [16]
  2. Noncoding RNA: ncRNA is another key signature of epigenetic gene regulation. It plays an active role in controlling gene expression (up-regulation and down-regulation), translation, splicing, and catalysis in cells, but is not translated into proteins [1]. The aberrant activity of ncRNA is associated with many diseases, including cancer, lupus, rheumatoid arthritis, and multiple sclerosis [16].
  3. Histone post-translational modification: A nucleosome is formed by 147 bp of DNA wrapped around histone complexes consisting of two unstable dimers of histones (H2A and H2B), a tetramer of histones (H3), and H4 [16]. The modification of histone proteins, such as acetylation, methylation, ubiquitination, phosphorylation, and SUMOylation, is another vital element of regulating gene expression [17]. Histone acetylation represents active gene expression, whereas deacetylation represses gene expression. The presence of methylation on histones can indicate both active and inactive transcription, and the state of mono-, di-, and trimethylation has different effects. Any aberration in histone modification can lead to the development of diseases, such as cancers, autoimmune diseases, endocrine diseases, and psychological disorders [16].

Methods to Study Epigenetic Signatures

Several methods have been developed to investigate epigenetic signatures (DNA methylation, histone modifications, and ncRNA). Some of the most commonly used methods are listed here:

  1. Microarray-based methylation assessment of single samples (MMASS) [18]: MMASS restriction enzyme- and microarray-based method is used to identify the ratio of methylated to unmethylated DNA fragments in a given sequence of a single sample.
  2. Methylation-sensitive amplified fragment length polymorphism (MS-AFLP) [18]: MS-AFLP is a highly sensitive and consensus method for detecting DNA methylation.
  3. Differential methylation hybridization (DMH) [18]: The DMH method helps to identify changes at the whole-genome methylation level, resulting in epigenetic alterations.
  4. Comprehensive high-throughput arrays for relative methylation (CHARM) [18]: CHARM is more suitable and precise for detecting methylated CpG on differentially methylated regions.
  5. High-resolution melting (HRM) [18]: HRM detects the methylation status of amplicons that is directly determined via the descending temperature during denaturation to renaturation. It is also able to detect the presence of single nucleotide polymorphism in DNA.
  6. Chromatin immunoprecipitation assay (ChIP) [18]: The ChIP assay is a popular method for analyzing protein-DNA interactions, identifying the locations of histone modifications on DNA, and controlling transcription.
  7. DNA-hypersensitivity assay (DHS) [18]: DHS is a powerful technique for the analysis of the open structure of chromatin and genomic regulatory processes. 
  8. RNA sequencing [19]: RNA sequencing is the key to identifying novel ncRNA in the genome.
  9. RNA interference (RNAi) [19]: RNAi is the backbone of studying the regulatory function of ncRNA.
  10. CRISPR inhibition/activation (CRISPRi/a) [19]: CRISPRi/a is the advanced methodology used to study the function of ncRNA in its regulatory role.

Epigenetic biomarkers in the clinical setting

Many epigenetic biomarkers are already in clinical use in preventing, diagnosing, and treating many diseases. Here are the key advantages of epigenetic biomarkers:

  1. Epigenetic biomarkers correlate with genetic and environmental factors contributing to disease development.
  2. Testing epigenetic biomarkers is easy as they can be checked in blood, tissue, body fluid, and secretions.
  3. Any change in epigenetic biomarkers can be detected at an earlier stage of a disease, which is not easily done in RNA and protein-based markers.

Epigenetics in disease

Epigenetic aberration is a common feature in many diseases. Here is a list of common diseases where epigenetics play a role:

  1. Acute Myeloid Leukemia (AML) [16]: AML is a classic example of how aberration of the epigenetic landscape leads to disease development. Studies have shown that disruption of DNA methylation in a CpG island is a key contributing factor leading to AML [20]. Hence, to achieve better patient management, there is an urgent need to unearth the epigenetic mechanisms and pathogenesis of AML. 
  2. Lung Cancer [16]: Lung cancer is the leading cause of tumor-related death worldwide and is responsible for nearly 30% of cancer-related deaths. The interaction of genetic disruption and dynamic epigenetic aberrancies may contribute to the aberrant onset and development of lung cancer [21]. Epigenetics plays a significant role and is an appealing target for the development of novel therapies in lung cancer. 
  3. Systemic Lupus Erythematosus (SLE) [16]: Epigenetics can play a key role in unlocking the molecular mechanism behind the development of SLE [22]. Recent studies have shown that the aberration of MCEP2 leads to the development of SLE. MCEP2 impacts all three epigenetic signatures: DNA methylation, ncRNA, and histone modification [1,14].
  4. Rheumatoid Arthritis (RA) [16]: RA is characterized by the immune system's abnormal targeting of joint linings. One of the common observations in stromal and immune cells in RA is the disruption of DNA methylation, histone modifications, and ncRNA. Multiple inflammatory and matrix-related pathways are impacted by epigenome aberration, which aids in the development of RA [23]. Hence, epigenetics has become a pivotal player to be investigated for novel drug targets in RA.
  5. Multiple Sclerosis (MS): MS is characterized by axonal degeneration and demyelination that affects the nerves of the brain and spinal cord. It is a chronic autoimmune disease. Disruption of epigenetic profiles in the immune system leading to demyelination and recurrent inflammation that contributes to the pathogenesis of MS has been reported by many researchers [24-27]. 

Epigenetic Therapy

With the advancement in the understanding of epigenetics, novel drugs are being developed by targeting epigenetic signatures; these drugs are called epidrugs.

The most common epidrugs are inhibitors of histone deacetylase and DNAMT. The first epidrugs to be approved by the US Federal Drug Administration (FDA) for the treatment of leukemia were inhibitors to DNMT and known as azacytidine (5-AZA) and decitabine (5-AZA-CdR) in 2004. Since then, the FDA has approved many other epidrugs, while others are in clinical trials. 


The advancement in technology has allowed for the generation of massive amounts of data that could be used to investigate intricate maps of both genetic risk and epigenetic associations in chronic disease states.

A robust computational metanalysis of 39 genome-wide association studies (GWAS) found that 69% of single nucleotide polymorphisms were shared among at least two autoimmune diseases [28]. The analysis computed a genome-wide map of histone post-translational modification regulatory elements and performed clustering of individual cell types based on these patterns [28]. We will undoubtedly see more of these integrated analyses in the future as the costs of whole-genome sequencing and base-specific whole-genome epigenetic analyses continue to decline. Hopefully, this will lead to a more thorough understanding of the fundamental mechanisms of disease pathogenesis, driven by machine learning insights and perhaps even novel treatment approaches.

For more information on the clinical applications of these advances in epigenetics, go to homehope.org



  1. Jeffries, M. A. The development of epigenetics in the study of disease pathogenesis. Epigenetics in Allergy and Autoimmunity 57–94 (2020).

  2. Paweletz, N. Walther Flemming: pioneer of mitosis research. Nat Rev Mol Cell Biol 2, 72–75 (2001).

  3. Muller, H. J. Types of visible variations induced by X-rays in Drosophila. J Genet 22, 299–334 (1930).

  4. McClintock, B. The origin and behavior of mutable loci in maize. Proceedings of the National Academy of Sciences 36, 344–355 (1950).

  5. Hannah, A. Localization and function of heterochromatin in Drosophila melanogaster. Adv Genet 4, 87–125 (1951).

  6. Nanney, D. L. Epigenetic control systems. Proceedings of the National Academy of Sciences 44, 712–717 (1958).

  7. Kornberg, R. D. & Thomas, J. O. Chromatin Structure: Oligomers of the Histones: The histones comprise an (F2A1) 2 (F3) 2 tetramer, a different oligomer of F2A2 and F2B, and monomer of F1. Science (1979) 184, 865–868 (1974).

  8. Holliday, R. & Pugh, J. E. DNA Modification Mechanisms and Gene Activity During Development: Developmental clocks may depend on the enzymic modification of specific bases in repeated DNA sequences. Science (1979) 187, 226–232 (1975).

  9. Riggs, A. D. X inactivation, differentiation, and DNA methylation. Cytogenet Genome Res 14, 9–25 (1975).

  10. Holliday, R. A new theory of carcinogenesis. Br J Cancer 40, 513–522 (1979).

  11. Jones, P. A. Altering DNA methylation with 5-azacytidine. Cell 40, 485–486 (1985).

  12. Lee, R. C., Feinbaum, R. L. & Ambros, V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).

  13. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

  14. Koelsch, K. A. et al. Functional characterization of the MECP2/IRAK1 lupus risk haplotype in human T cells and a human MECP2 transgenic mouse. J Autoimmun 41, 168–174 (2013).

  15. Horvath, S. DNA methylation age of human tissues and cell types. Genome Biol 14, 1–20 (2013).

  16. Zhang, L., Lu, Q. & Chang, C. Epigenetics in health and disease. Epigenetics in allergy and autoimmunity 3–55 (2020).

  17. Park, J., Lee, K., Kim, K. & Yi, S.-J. The role of histone modifications: From neurodevelopment to neurodiseases. Signal Transduct Target Ther 7, 217 (2022).

  18. Halabian, R. et al. Laboratory methods to decipher epigenetic signatures: a comparative review. Cell Mol Biol Lett 26, 1–30 (2021).

  19. Marx, V. Some roads ahead for noncoding RNAs. Nat Methods 19, 1171–1174 (2022).

  20. Duy, C., Béguelin, W. & Melnick, A. Epigenetic mechanisms in leukemias and lymphomas. Cold Spring Harb Perspect Med 10, a034959 (2020).

  21. Shi, Y.-X., Sheng, D.-Q., Cheng, L. & Song, X.-Y. Current landscape of epigenetics in lung cancer: focus on the mechanism and application. J Oncol 2019, (2019).

  22. Montoya, T., Castejón, M. L., Muñoz-García, R. & Alarcón-de-la-Lastra, C. Epigenetic linkage of systemic lupus erythematosus and nutrition. Nutr Res Rev 1–21 (2021).

  23. Nemtsova, M. V et al. Epigenetic changes in the pathogenesis of rheumatoid arthritis. Front Genet 10, 570 (2019).

  24. Ma, Q., Oksenberg, J. R. & Didonna, A. Epigenetic control of ataxin‐1 in multiple sclerosis. Ann Clin Transl Neurol 9, 1186–1194 (2022).

  25. Eslahi, M., Nematbakhsh, N., Dastmalchi, N., Teimourian, S. & Safaralizadeh, R. An Updated Review of Epigenetic-Related Mechanisms and Their Contribution to Multiple Sclerosis Disease. CNS & Neurological Disorders-Drug Targets (Formerly Current Drug Targets-CNS & Neurological Disorders) (2023).

  26. Kular, L. & Jagodic, M. Epigenetic insights into multiple sclerosis disease progression. J Intern Med 288, 82–102 (2020).

  27. Jamebozorgi, K. et al. Epigenetic aspects of multiple sclerosis and future therapeutic options. International Journal of Neuroscience 131, 56–64 (2021).

  28. Farh, K. K.-H. et al. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 518, 337–343 (2015).


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