Epigenetics offers a framework for understanding how gene expression can be modified without altering the underlying DNA sequence (Gibney & Nolan, 2010). This concept is fundamental because nearly all cells within an organism contain the exact genetic blueprint, yet specialized cells activate only the subset of genes necessary for their specific identity and function. While some epigenetic changes might be transient within a single cell, many such modifications can be stable through mitosis, ensuring that cellular identity is maintained (Allis & Jenuwein, 2016). Even with a complete understanding of how DNA sequence variations affect gene function, comprehending epigenetics is necessary to explain the patterns of gene activity observed in organisms. Various mechanisms contribute to this layer of gene regulation.

Several types of epigenetic mechanisms influence gene function, including DNA methylation (Gibney & Nolan, 2010), histone modification (Allis & Jenuwein, 2016), and non-coding RNA sequences. Molecules such as microRNAs and long non-coding RNAs can influence gene expression without being translated into proteins themselves (Allis & Jenuwein, 2016). LncRNAs can have various roles, like guiding chromatin-modifying complexes to specific locations.

The potential for such epigenetic effects to persist across generations is known as transgenerational epigenetic inheritance. This can vary considerably among the mentioned mechanisms. For DNA methylation, patterns are generally maintained through mitosis within an individual, contributing to stable cell lineages (Allis & Jenuwein, 2016). However, during germline development and early embryogenesis in mammals, extensive demethylation and subsequent remethylation reprogram the epigenome, erasing most parental methylation patterns (Heard & Martienssen, 2014). While some loci might escape reprogramming, allowing for potential inheritance, it is not considered a widespread phenomenon for most genes (Heard & Martienssen, 2014). Histone modifications are also largely reset during gametogenesis. Although some histone marks might persist in sperm or egg cells, conclusive evidence for their stable transmission and functional impact across multiple generations in mammals is limited compared to the maintenance observed within an individual’s somatic cells (Heard & Martienssen, 2014). Non-coding RNAs can be packaged into gametes and might influence the development of the immediate offspring, but their concentration typically diminishes with subsequent cell divisions, making stable inheritance over many generations improbable for most ncRNAs (Heard & Martienssen, 2014). Chromatin remodeling complexes act dynamically, and their specific configurations are unlikely to be directly inherited through gametes; the chromatin states they establish are generally reset during germline reprogramming. Therefore, while all these mechanisms contribute significantly to gene regulation within an individual and maintain cell identity through mitosis, their stable inheritance across generations through meiosis is generally limited in mammals (Heard & Martienssen, 2014).

Each of the above mechanisms can change gene function, often by influencing the rate of transcription and the amount of gene product produced. DNA methylation, mainly occurring at CpG islands, is commonly associated with gene silencing (Gibney & Nolan, 2010). The methyl groups can directly interfere with the binding of transcription factors or recruit methyl-binding proteins that recruit repressive complexes, leading to chromatin condensation and a decrease in the gene product. The lack of methylation in these regions permits transcription, sometimes leading to an increase in gene product as long as the appropriate activators are present (Gibney & Nolan, 2010). For example, histone modifications can alter chromatin structure. Histone acetylation cancels out the positive charge of lysine residues on histone tails. This weakens the interaction with DNA, which is negatively charged. This increases accessibility for transcription factors and RNA pol, causing an increase in the gene product (Gibney & Nolan, 2010). Deacetylation reverses the effect, compacting chromatin and leading to a decrease in the gene product. Histone methylation can have opposing effects depending on the specific amino acid residue methylated and the degree of methylation; for instance, methylation of histone H3 at lysine 9 (H3K9me3) is typically a repressive mark associated with heterochromatin and a decrease in gene product, whereas methylation of H3 at lysine 4 (H3K4me3) is often found near active promoters and associated with an increase in gene product (Allis & Jenuwein, 2016). Non-coding RNAs and miRNAs mainly function post-transcriptionally, wherein a specific miRNA binds to complementary sequences in the 3′ region of a target mRNA, leading either to the degradation of the mRNA or the inhibition of its translation into protein, both resulting in a decrease in gene product (Allis & Jenuwein, 2016). Chromatin remodeling complexes directly alter nucleosome positioning. By shifting or removing nucleosomes from promoter or enhancer regions, they can expose regulatory DNA sequences, which facilitate transcription factor binding and causes an increase in the gene product. They can also decrease gene expression by positioning nucleosomes to obscure these sites (Allis & Jenuwein, 2016).

Variations in the expression of the TPMT gene can increase bone marrow toxicity in patients treated with thiopurine immunosuppressant drugs. Thiopurines are commonly used in treating autoimmune diseases, inflammatory bowel disease, and certain cancers. The TPMT enzyme provides an inactivation pathway that converts the drugs into inactive methylated metabolites. The inactivation pathway is impaired if the amount of TPMT gene product is decreased, which occurs in individuals with specific genetic variants that lead to lower-than-average enzyme activity. This results in shunting the drug metabolism towards the production of higher levels of the active, cytotoxic TGNs. In this case, TGN accumulates in hematopoietic progenitor cells within the bone marrow, increasing cytotoxicity. This then manifests as severe bone marrow suppression. Bone marrow suppression is characterized by severe leukopenia, thrombocytopenia, and anemia. These symptoms can increase the risk of life-threatening infections and bleeding (Relling et al., 2019).

However, if the TPMT gene product were to be greatly improved, this would lead to high enzyme activity, inactivating the thiopurine drugs too quickly. This would lower intracellular concentrations of active TGNs and diminish the drug’s therapeutic effectiveness at normal doses. The safe and effective dosing of thiopurine drugs heavily depends on our understanding of the level of TPMT function (Relling et al., 2019).

References

Allis, C. D., & Jenuwein, T. (2016). The molecular hallmarks of epigenetic control. Nature Reviews Genetics, 17(8), 487–500. https://doi.org/10.1038/nrg.2016.59  

Gibney, E. R., & Nolan, C. M. (2010). Epigenetics and gene expression. Heredity, 105(1), 4–13. https://doi.org/10.1038/hdy.2010.54

Heard, E., & Martienssen, R. A. (2014). Transgenerational epigenetic inheritance: myths and mechanisms. Cell, 157(1), 95–109. https://doi.org/10.1016/j.cell.2014.02.045

Relling, M. V., Schwab, M., Whirl-Carrillo, M., Suarez-Kurtz, G., Pui, C. H., Stein, C. M., Moyer, A. M., Evans, W. E., Klein, T. E., Antillon-Klussmann, F. G., Caudle, K. E., Kato, M., Yeoh, A. E. J., Schmiegelow, K., & Yang, J. J. (2019). Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes. Clinical Pharmacology & Therapeutics, 105(5), 1095–1105. https://doi.org/10.1002/cpt.1304