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Epigenetics

From Archania
Epigenetics
Disciplines Genetics, Molecular biology
First description Conrad Waddington (1942)
Applications Medicine, cancer research, aging, regenerative medicine
Mechanisms DNA methylation, Histone modification, non-coding RNAs
Description Heritable changes in gene activity without altering the DNA sequence.
Wikidata Q26939

Epigenetics is a branch of Biology that studies heritable changes in gene function that do not involve alterations of the DNA sequence. It examines how DNA is transcribed and expressed, focusing on biochemical mechanisms that activate or silence Genes—notably DNA methylation and Histone modification.[1] An epigenetic trait is a stably inherited Phenotype not caused by DNA sequence change.

The diagram shows active DNA without methylation and inactive DNA with methyl groups (Me), which regulate gene expression.

An illustrative example of epigenetic changes is the differentiation of different cell types in tissues and organs during the development of multicellular organisms. Here, epigenetic modifications affect which genes are active in certain cell types. Environmental influences can also cause such epigenetic changes, and this may be a contributing factor to the fact that inherited diseases such as Schizophrenia do not always affect both twins in an identical Twin pair, even though they are genetically identical.

Epigenetic processes also play an important role in aging. As cells age, epigenetic changes such as methylation and histone modifications accumulate. These changes affect gene expression and can lead to loss of function in tissues and organs, which may contribute to the development of autoimmune diseases, Diabetes, Cancer, Dementia, and other age-related diseases[2].

Maternal epigenetic contributions and zygotic reprogramming

During early embryogenesis, most parental epigenetic marks undergo global demethylation and later re-establishment; notable exceptions include imprinted loci and certain repeats.[3]

Epigenetics plays a crucial role in early development, and the maternal epigenetic contribution is often considered to be particularly important. The egg, which contains nutrients, Organelles, and extensive epigenetic information, serves as the primary environment for the development of the zygote. When the sperm fertilizes the egg, the sperm chromosomes are assimilated into the egg environment, and much of the epigenetic information from the sperm is removed through a mechanism called demethylation. This occurs to "reset" genetic information and adapt it to the egg environment. At the same time, the egg retains some of its own methylations and histone modifications, which form the basis for further development[4].

The image illustrates the process by which a sperm cell fertilizes an egg cell and forms a zygote. The image shows how the female egg cell functions as the original epigenetic environment in early development.

This asymmetry means that the mother's genetic and epigenetic contributions often have a dominant role in early development. Studies show that this affects gene expression throughout the organism's life cycle. Environmental influences on the mother before and during pregnancy can also change the epigenetic patterns in the egg cells and thus affect the development and health of the offspring[5][6].

In early fetal life, epigenetic modifications are selectively removed. This ensures that cells can restore their pluripotency and develop into different cell types. Not all epigenetic markers are removed – imprinted genes and important regulatory sequences retain their modifications. Differentiation leads to new patterns of methylation and gene regulation, which maintain specific cell functions. However, certain environmental influences can lead to heritable epigenetic changes across generations.

Communication between the fetus and the mother also plays an important role in the epigenetic regulation of fetal development. The fetus can send signals through hormones and growth factors, which affect how the mother’s body allocates nutrients and resources. At the same time, the mother’s body can adjust the resource supply based on the fetus’s developmental needs and environmental conditions. This dynamic communication can influence how epigenetic patterns, such as DNA methylation and histone modifications, are established in the fetus’ cells. If the fetus experiences a shortage of resources, this can lead to epigenetic adaptations that affect its physiology and health later in life. Such mechanisms may be part of fetal programming and may also contribute to transgenerational effects[7].

Metabolism–epigenome crosstalk (mitochondria)

Mitochondria, which are mainly maternally inherited, play a crucial role in cellular energy production and metabolism. In addition, they are important for epigenetic regulation of gene expression. Among other things, mitochondria influence the levels of metabolites (such as Acetyl-CoA, NAD+, and Α-ketoglutarate), which are necessary cofactors for a number of epigenetic enzymes, including DNA and histone demethylases[8].

Mitochondria also have their own genome (mtDNA), which can undergo epigenetic modifications, including methylation. Although mtDNA is relatively small and circular compared to nuclear DNA, changes in mtDNA methylation and mitochondrial function can potentially affect nuclear gene expression through an interaction known as “mitonuclear crosstalk”[9]. When mitochondria experience stress or dysfunction (for example, oxidative stress), this can lead to changes in epigenetic patterns in both mtDNA and nuclear genes, which may have consequences for development, cellular differentiation, and disease development.

Furthermore, maternal inheritance of mitochondria is thought to result in specific metabolic conditions in the egg, and later in the developing zygote, setting the stage for epigenetic modifications in the fetus. Both mitochondrial biogenesis and dynamics (mitochondrial division and fusion) are tightly regulated during embryonic development, and these processes can influence the establishment of epigenetic patterns.[10]. Thus, the role of mitochondria in gene regulation is not limited to energy supply, but also includes active participation in epigenetic programming that affects development, health, and possible transgenerational effects.

Paternal inheritance and environmental influences

There is research that suggests that environmental influences experienced by men can lead to heritable epigenetic changes. A study from the northern Swedish town of Överkalix showed that the sons of men who had experienced childhood hunger were less likely to develop Cardiovascular disease. In men with ample access to food during childhood, an increased Risk of diabetes was observed in male grandsons[11][12]. The results suggest that epigenetic markers in sperm can be influenced by past environmental conditions. However, the field is still under active research, and more studies are needed to confirm such relationships.

One proposed mechanism is that MicroRNA and other small RNAs in sperm can transmit information about the father’s environment to the embryo. Experimental studies in mice have shown that stress, diet, or toxin exposure in males can alter sperm RNA content, and injection of these RNAs into fertilized eggs can reproduce the offspring phenotypes[13][14]. These findings indicate that paternal environmental exposures may influence the next generation not only through DNA methylation, but also via RNA-based epigenetic signals.

Nevertheless, such patterns may also be partly due to the indirect influence of fathers on the child's environment and culture. For example, habits and attitudes related to food, physical activity, and stress management can influence how epigenetic patterns are transmitted across generations.

Psychoneuroimmunology and epigenetics

Recent research suggests that epigenetic mechanisms are influenced not only by diet and physical environment, but also by psychological and social factors. This is central to the field of psychoneuroimmunology (PNI), which studies how psychological processes, the nervous system, and the immune system influence each other. Findings suggest that chronic stress can induce epigenetic changes that can increase the risk of a number of diseases, including autoimmune disorders, depression, and cancer[15].

Among the mechanisms linking PNI and epigenetics are:

  • Stress hormones and DNA methylation: Elevated levels of cortisol and other stress hormones can affect methylation patterns in genes related to immune function, which can reduce the body's ability to fight infections or lead to chronic inflammation.
  • Inflammation-regulating genes: Epigenetic modifications of genes encoding proinflammatory cytokines (such as IL-6 and TNF-α) can increase or decrease levels of inflammation in the body, and stress is thought to influence these processes.
  • Long-term effects of childhood stress: Studies suggest that trauma or chronic stress in childhood can produce epigenetic changes that manifest in adulthood. Such changes can affect how the nervous system and immune system respond to new stresses[16].

These findings open up new possibilities in prevention and treatment, where stress management, psychotherapy and other psychosocial interventions may have a beneficial effect on epigenetic processes and thus on immune function.

References

  1. ↑ Berger, S.L., Kouzarides, T., Shiekhattar, R., & Shilatifard, A. (2009). "An operational definition of epigenetics". Genes & Development, 23(7), 781–783. doi:10.1101/gad.1787609
  2. ↑ López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., & Kroemer, G. (2013). "The hallmarks of aging". Cell, 153(6), 1194-1217. doi:10.1016/j.cell.2013.05.039
  3. ↑ Reik, W., Dean, W., & Walter, J. (2001). Science, 293(5532), 1089–1093. doi:10.1126/science.1063443
  4. ↑ Reik, W., Dean, W., & Walter, J. (2001). "Epigenetic reprogramming in mammalian development". Science, 293(5532), 1089-1093. doi:10.1126/science.1063443
  5. ↑ Barton, S.C., Surani, M.A., & Norris, M.L. (2004). "Epigenetic inheritance in mammals". Nature Reviews Genetics, 5(2), 128-138. doi:10.1038/nrg1272
  6. ↑ Skinner, M.K. (2008). "Environmental epigenomics and disease susceptibility". Nature Reviews Genetics, 9(8), 689-698. doi:10.1038/nrg2430
  7. ↑ Gluckman, P.D., & Hanson, M.A. (2004). "Living with the Past: Evolution, Development, and Patterns of Disease". Science, 305(5691), 1733-1736. doi:10.1126/science.1095292
  8. ↑ Scarpulla, R. C., Vega, R. B., & Kelly, D. P. (2012). "Transcriptional integration of mitochondrial biogenesis". Trends in Endocrinology & Metabolism, 23(9), 459-466. doi:10.1016/j.tem.2012.06.006
  9. ↑ Kelly, R. D. W., Mahmud, A., McKenzie, M., Trounce, I. A., & St John, J. C. (2012). "Mitochondrial DNA Copy Number Is Regulated in a Tissue-Specific Manner by DNA Methylation in Humans". Epigenetics, 7(4), 442-450. doi:10.4161/epi.19533
  10. ↑ Wallace, D. C. (2005). "A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine". Annual Review of Genetics, 39, 359-407. doi:10.1146/annurev.genet.39.110304.095751
  11. ↑ Kaati, G., Bygren, L.O., & Edvinsson, S. (2002). Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ slow growth period. Eur J Hum Genet, 10, 682–688.
  12. ↑ Pembrey, M.E., et al. (2006). Sex-specific, male-line transgenerational responses in humans. Eur J Hum Genet, 14, 159–166.
  13. ↑ Gapp, K., Jawaid, A., Sarkies, P. et al. Implication of sperm RNAs in transgenerational inheritance of the effects of early trauma in mice. Nat Neurosci 17, 667–669 (2014).
  14. ↑ Chen, Q., Yan, W., & Duan, E. Epigenetic inheritance of acquired traits through sperm RNAs and sperm RNA modifications. Nat Rev Genet 17, 733–743 (2016).
  15. ↑ Meaney, M.J. (2010). "Epigenetics and the biological definition of gene × environment interactions". Child Development, 81(1), 41–79. doi:10.1111/j.1467-8624.2009.01381.x
  16. ↑ Weaver, I.C.G., et al. (2004). "Epigenetic programming by maternal behavior". Nature Neuroscience, 7(8), 847-854. doi:10.1038/nn1276
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