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Genetics and ... the Missing Link ... Epigenetics

Transcription, translation and subsequent protein modification represent the transfer of genetic information from the archival copy of DNA to the short-lived messenger RNA, usually with subsequent production of protein. Although all cells in an organism contain essentially the same DNA, cell types and functions differ because of qualitative and quantitative differences in their gene expression. Thus, control of gene expression is at the heart of differentiation and development. Epigenetic processes, including DNA methylation, histone modification and various RNA-mediated processes, are thought to influence gene expression chiefly at the level of transcription; however, other steps in the process (for example, translation) may also be regulated epigenetically. (Gibney ER and Nolan CM Epigenetics and gene expression, Heredity, 2010).

PSGR was established at around the same time the Human Genome Project (HGP) mapped the human genome. HGP data showed us that genetic heredity played a much smaller role in driving health and disease than previously presumed and that often dozens if not hundreds of genes might play a role in disease aetiology.

Genes are driven by a vast array of physiological drivers – epigenetic processes, which act to modify gene expression and phenotype (physiological characteristics), turning genes on and off - and influencing how they work. The DNA or gene sequence remains unchanged. Epigenetics loosely translated, means ‘above the gene.’

Humans have one genome, and hundreds of epigenomes (Ficz 2015). Epigenetics was first described by embryologist Conrad Waddington in 1942, Conrad Waddington as ‘the complex of developmental processes between the genotype and phenotype’ (Deichmann 2016).

‘epigenetics refers to both heritable changes in gene activity and expression (in the progeny of cells or of individuals) and also stable, long-term, alterations in the transcriptional potential of a cell that are not necessarily heritable’

While the genome is identical and stable in vertebrates, the epigenome differs from cell to cell and is plastic, changing with time and with exposure to the environment (Gibney & Nolan 2010). Epigenetics challenges us because epigenetic marks are not transmitted through cell division or the germ line, and the precise definition of epigenetics and gene expression remains contested (Deichmann 2016).  

Almost daily, scientists are demonstrating that DNA as genetic instructions of cellular biology, are only the tip of the iceberg when discussing human (and environmental) biology, from evolution to disease development. It is now understood that a liver cell is initially the same as a fingernail cell. The development and function of all living things are not solely dependent on our genetic instructions, but on epigenetic influences that arise from environmental exposures.

(Paper 'When is a gene not DNA?' by Professor Jack Heineman)

Epigenetics has been referred to as the ‘missing link between genetics, the environment, and endocrine functions’ (Zhang 2011). When a tadpole changes into a frog, the tadpole produces a surge of thyroid hormone which, as Dr Barbara Demeneix explains, turns into a series of epigenetic switches.

‘The epigenetic changes do not alter any DNA sequence, but they turn off certain genes and turn on others’ (Demeneix 2017, p.120). 

In the long debate of nature versus nurture, scientists considered that our phenotype – who we are as a result of our genes and environment, was predominantly due to the influence of genes - genetic inheritance (recognised as Darwinian natural selection or Mendelian inheritance). Yet the relatively new field of epigenetics is clearly challenging this, and evidence that epigenetic traits can be inherited (without changing the gene) further muddies the (gene) pool. It is complicated, for example genetic sequences can influence subsequent developmental epigenetic events (Ficz 2015). 

With this relatively new field of science, humanity doesn’t just need to know what is happening within the cell, we also need to understand what is going on in and between cells – rather than cellular biology – it’s molecular biology. Instead of acting as a closed loop within a neat biological system, our bodies constantly respond and interact to both our internal biological environment and the external environment.

The vast majority of environmental factors and toxicants do not have the ability to alter DNA sequence or promote genetic mutations. In contrast, the environment can dramatically influence epigenetic processes to alter gene expression and development. Therefore, epigenetics provides a molecular mechanism for the environment to directly alter the biology of an organism (Skinner 2014). 

Gene expression is at the heart of differentiation and development. Gibney and Nolan's Review, Epigenetics and Gene Expression (2010), succinctly lays out the core mechanisms: DNA methylation, histone modifications, and RNA‑mediated regulation.

DNA methylation: Leads to transcriptional upregulation, silencing via multiple mechanisms. 

DNA methylation is an epigenetic mechanism where methyl groups are added to cytosine bases, usually at CpG sites. When this occurs in promoter regions, it typically represses transcription by blocking transcription factor binding or attracting silencing proteins. Methylation doesn't always block or silence. In gene bodies, it can correlate with active transcription, possibly by maintaining gene stability. At enhancers, methylation usually reduces activity, while demethylation can lead to upregulation of distant genes. Methylation patterns are essential for development, X-chromosome inactivation, and silencing repetitive elements. They are heritable through cell division but responsive to environment, ageing, and disease. DNA methylation helps fine-tune gene expression—either silencing or supporting it—depending on genomic context.

Promoter methylation occurs just upstream of the gene (where transcription starts). Most frequently silencing the gene and switching it off. Gene body methylation occurs inside the gene (after the transcription commencement site). Often correlated with active transcription (can suppress spurious internal start sites and help with transcriptional efficiency), and the gene is typically on and stable. Regulatory DNA is any segment of DNA that helps control when, where, and how much a gene is expressed. It doesn’t code for proteins itself, but it controls the genes that do. Regulatory DNA is a category, encompassing nearby promoters, (and potentially far away) enhancers, silencers, insulators and operators (in bacteria), while for example, enhancers are the most well-known regulatory DNA. However, silencers, insulators, and locus control regions can also regulate transcription at a distance by shaping the 3D structure of the genome. Enhancer methylation occurs at regulatory DNA far from the gene it controls - upstream, downstream including within unrelated genes using chromatin looping to contact promoters. Silencers which repress gene expression, can also act over long distances and use chromatin looping which inhibits promoter activity. Insulators define boundaries between regulatory domains and can potentially block enhancer-promoter interactions, and can help mediate chromatin architecture through the binding of certain proteins. Finally, locus control regions act as complex regulatory hubs that can coordinate multiple genes, also using looping to bring distant elements into the shared transcriptional environment. (Vermunt et al 2019, Splinter et al 2006, Kadauke and Blobel 2010).

Histone modifications: post-translational modification of histone proteins and remodelling of chromatin.

Histones are structural proteins, their job is to package (organise and compact) DNA into a structure, chromatin. DNA wraps around histones and this packaging impacts whether genes are accessible to the cellular machinery, that then makes proteins (RNA polymerase, which transcribes DNA into RNA). Therefore, histones indirectly control which proteins are made as they control access to the genes that encode them. 

Histone modification is an epigenetic mechanism that alters how tightly DNA is packaged in the nucleus, influencing gene expression. These are known as post-translational modifications because they occur after the protein is built. DNA wraps around proteins called histones, forming a structure known as chromatin. The ends of these histones—called tails—stick out and can receive chemical tags after the protein is made. Histones themselves are produced when histone genes are transcribed into messenger RNA (mRNA), which is then translated by ribosomes into protein. Once made, these histone proteins can be chemically modified—most commonly by the addition of acetyl, methyl, or phosphate groups. Such changes affect how the DNA–histone complex behaves: for example, acetylation generally loosens chromatin to allow gene activation, while methylation can either activate or silence genes, depending on the site. Histone modifications are reversible and dynamic, allowing cells to respond to signals and regulate genes without altering the DNA sequence itself. (Liu et al 2020, Bannister and Kouzarides 2011, Cavalieri 2021)

RNA‑mediated regulation:  RNA molecules can influence gene expression without altering the DNA sequence.

RNA-mediated epigenetic regulation refers to how certain RNA molecules influence gene expression without altering the DNA sequence. The most well-known are non-coding RNAs—including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs)—which don’t code for proteins but help control which genes are active or silent. miRNAs bind to messenger RNA (mRNA) to block translation or trigger degradation, reducing protein production. lncRNAs can recruit proteins that modify histones or DNA methylation patterns, guiding these changes to specific genes. Some RNAs also help form RNA–protein complexes that alter chromatin structure, switching genes on or off. These processes are vital in development, stem cell differentiation, and disease, especially cancer. Because RNA molecules can act precisely and reversibly, they offer powerful tools for fine-tuning gene expression through epigenetic pathways.(Holoch and Moazed 2015, Joh et al 2014, Bure et al 2022).

Allis and Jenuwein's paper The Molecular Hallmarks of Epigenetic Control (2016) substantially added to understanding of epigenetic regulation, detailing the enzymatic machinery, combinatorial code, 3D genome architecture, and disease relevance of epigenetic regulation, and effectively setting a framework for future research. 

  • Outlined the role of enzymes as writers, erasers, and readers, of histone marks—enzymes that add (e.g. KMTs, HATs), remove (HDACs, demethylases), and recognize post‑translational histone modifications to regulate chromatin structure and transcriptional states.
  • Outline the histone code hypothesis, which articulates that specific combinations and spatial context of histone modifications (e.g. H3K4me3 vs H3K27me3) generate distinct functional outcomes, influencing both activation and repression of genes via multivalent reader complexes
  • Clarified thinking about chromatin architecture by integrating histone modification research with higher-order genome structures, (such as Topologically Associated Domains (TADs) and pioneer transcription factors), to demonstrate how epigenetic marks cooperate within three-dimensional chromatin frameworks to stabilise gene expression programs.
  • Emphasised the transgenerational and germline dimensions of epigenetic control, referencing cases where histone modifications survive epigenetic reprogramming and may carry signals to subsequent generation.

New mechanisms of epigenetic modifications are likely to emerge, however the:

‘key mechanisms underlying epigenetic modifications include: chromatin remodeling, methylation of cytosinein CpG dinucleotides (often referred to as DNA methylation), histone tail N-terminal modification, and post-translational modification of genes regulation by non-coding/small RNA (ncRNA/sRNA). Collectively, these processes and the components upon which they act constitute the epigenome. Individually or in concert, they play a key role in turning gene expression on or off, thus facilitating or inhibiting the production of specific proteins'. (Norouzitallab et al 2019). 

 Examples of the emerging literature on man-made technologies interfering/disrupting epigenetic processes:

Radiofrequency field radiation - Studies reveal low-level, non-ionizing EMF exposure can lead to rapid epigenetic modifications:

Cantu et al 2023: DNA methylation patterns examined in human keratinocytes exposed to 900 MHz RF-EMFs for 1 h at a low dose rate. The low-dose exposure caused genome-wide DNA methylation changes in human skin cells. Six genes were identified which showed both methylation and expression alterations shortly after exposure—suggesting swift epigenetic signalling via RF exposure.

Ravaioloi et al 2023: Cell lines exposed to 900 MHz influenced DNA methylation in repetitive elements (LINE-1 -long interspersed nuclear elements-1) and ribosomal repeats in terms of both average profiles and organisation of methylated and unmethylated CpG sites, in different ways in each of the three cell lines studied. The authors observed epigenetic instability via shifts in methylation diversity, theorising that this was possibly driven by RF-induced reactive oxygen species (ROS).

Pesticide exposures:

Rohr et al 2024: This review showed that pesticides—including herbicides, insecticides, endocrine disruptors, and persistent organic pollutants— can alter DNA methylation, histone modifications, and miRNA expression in cell and animal models. Review highlighted that these changes often persist after exposure and mirror patterns seen in disease states.

Nilsson and Skinner 2014: Environmental insults can lead to epigenetic changes (abnormalities, or epimutations) that are in turn increase susceptibility to disease. These changes (epimutations) can be heritable and transmitted across generations, increasing disease risk in adult offspring. 

Thorson et al 2020: Demonstrated that epigenome-wide association studies (EWAS) can assist in finding biomarkers that are associated with transgenerational disease susceptibility. The study exposed rodents to a pesticide combination and looked at F3 generation differential DNA methylation regions (DMRs) in diseased and non-diseased rodents. The DMRs were disease specific. The pesticide combination promoted transgenerational testis disease, prostate disease, kidney disease, and the presence of multiple disease in the subsequent F3 generation great-grand offspring.

The developmental origins of health and disease (DOAD)

 

Humans are exposed to an unprecedented array of exposures from conception.  We have a far greater body-burden than our ancestors (apart from those for example, that historically worked in or lived near toxic industrial sites). The blood brain barrier often does not protect the brain from exposures, and the developing foetus often shares many of the same exposures as the mother. Pre-conception exposures can damage subsequent generations.

Specific periods (or windows) of vulnerability in developmental life stages where the foetus, and the developing child, but also teenagers, are more susceptible to toxic environmental exposures. (WHO 2008) In the first trimester of pregnancy, the foetus is most vulnerable (Demeneix 2017).  The impact of environmental chemicals on fertility is also recognised (Trasande 2019). 

The chemical body-burden of the mother is absorbed by the foetus. Infants and young children will frequently consume more than adults relative to their body-weight. As a result, they are exposed to higher doses (Grandjean et al 2007). Chemicals can also persist and bioaccumulate in the body (WHO UNEP 2013). 

Poor nutrition or environmental stressors increase risk for disease or syndrome states via toxic exposures.

Despite the insight that was gained from the HGP - genetic and molecular research for medicine or for industrial or agricultural applications trumps research exploring the complex drivers of disease - in humans or in agriculture. Research exploring the environmental drivers of health and disease remains low priority, even as technologies that could shed light on environmental and genetic drivers of disease have advanced. 

Risk from electromagnetic field (EMF) may more adversely harm the developing foetus, babies and children than adults, adversely altering growth and development. Increased brain risk may arise from babies and children having smaller skulls, thinner bone density in the skull and more embryonic stem cells. EMF exposure can decrease DNA repair, while increasing DNA damage and EMF exposure. The relationship between these effects and increased cell division in young children, suggest exposed children may be at heightened risk for cancer (Environmental Health Trust, European Parliamentary Research Service (2021)). 

Prenatal and postnatal chemical exposures can alter the way genes are expressed and predispose the individual to disease in later life. The 2007 Faroes Statement stated:

‘These epigenetic changes can cause lasting functional changes in specific organs and tissues and increased susceptibility to disease that may even affect successive generations'.

One of the earliest demonstrations of epigenetic influence was where mice parents’ (dams) diets were supplemented with B12, folic acid, choline and betaine. The phenotype was altered as a result, and the obese, yellow parent gave birth to brown offspring (Waterland and Jirtle 2003). 

 

 

Image: James, P; Silver, M; Prentice, A (2018) Epigenetics, Nutrition, and Infant Health. In: The Biology of the First 1,000 Days. CRC Press, Boca Raton, FL, USA, p.341. ISBN 9781498756792

Epigenetic processes impact all cellular functions; however many scientists are focussing on neurodevelopmental exposures which can result in neurological damage and IQ loss. Early life epigenetic changes can influence later gene expression in the brain (Roth 2012).  Neurodevelopmental damage frequently arises via endocrinologic processes. Harm from endocrine disruption from environmental chemicals including delay and IQ loss, has been estimated at as much of 2% of global GDP. (Attina et al 2016)

The environmental aetiology of disease - how environmental stressors (see Figure 22.3) shape and contribute to disease is poorly understood, and research in this area, in contrast to studies funding for the genetic causes of disease, is poorly funded (Demeneix 2017). 

‘The root causes of the present global pandemic of neurodevelopmental disorders are only partly understood. Although genetic factors have a role, they cannot explain recent increases in reported prevalence, and none of the genes discovered so far seem to be responsible for more than a small proportion of cases' (Grandjean and Landrigan 2014). 

 Intergenerational Effect

Science is very clear that a wide range of chemicals not only exert epigenetic influences on the generation exposed to the particular chemical, but that these epigenetic influences can be carried through, in a process described as transgenerational epigenetic inheritance, to subsequent generations. For example, exposing a parent rat to the endocrine disrupting fungicide vinclozolin resulted in higher disease incidence in the great and great-great grand offspring (F3 and F4 generation) who were never exposed to the chemical.  The transgenerational inheritance was paternally transmitted via sperm, altering non-coding RNA (Schuster et al 2016) (Skinner 2014). 

As such, with full awareness of the potential intergenerational consequences of harmful exposures, it is becoming rather critical to understand the ‘exposome’ - our cumulative environmental exposures over a lifetime. Epigenetic mechanisms don’t only push one way, many epigenetic modifications may be reversible.

Governments and regulators in the areas of toxicity and risk assessment are yet to address epigenetics and the potential for chemical mixtures in food and environment to adversely affect biological function.

Dedicated public funding is required to address the environmental drivers of disease, the toxic exposures and stressors (among other things) that directly influence not only the development of mutations to the DNA in our cells, but also the way chemical mixtures drive harm, damaging developmental and driving disease pathways.

This knowledge has the potential to change how civil society and governance approach non-communicable disease and how governments address health policy. It is already driving pharmaceutical enterprise, there is a burgeoning field of epigenetic medicine and therapy.

This new molecular spotlight naturally draws attention to the role nourishing food plays, complete with essential minerals and vitamins - which we can now observe acting epigenetically. However, this also explains the toll on bodies of a bad diet, stress, chemicals and toxins.

Complex chemical mixtures such as personal care products and pesticides consumed in daily lives undergo very little regulation.  They are not assessed for potential to influence delicate molecular level epigenetic functioning, particularly in relation to the endocrine system (Kortencamp and Faust 2018). 

 

Paper: When is the gene not DNA?
Professor Jack Heinemann
Lecturer in Genetics
University of Canterbury, New Zealand

When is the gene not DNA? 

Download

References

Attina et al 2016. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. Lancet Diabetes Endocrinol 2016; 4: 996–1003

ERMA (2004) Transfer Notice. Hazardous Substances (pesticides) Transfer Notice 2004. Issue No. 72. P.1645-1718 https://www.epa.govt.nz/assets/Uploads/Documents/Hazardous-Substances/Policies/Hazardous-Substances-Pesticides-Transfer-Notice-2004.pdf

Ficz, G. (2015) New insights into mechanisms that regulate DNA methylation patterning. Journal of Experimental Biology 2015 218: 14-20; doi: 10.1242/jeb.107961

Grandjean et al 2008. The Faroes Statement: Human Health Effects of Developmental Exposure to Chemicals in Our Environment. Basic & Clinical Pharmacology & Toxicology. 102(2):73-5. doi: 10.1111/j.1742-7843.2007.00114.x.

Grandjean, P., Landrigan, P.J. (2014) Neurobehavioural effects of developmental toxicity. Lancet Neurol. 2014:13, 330–338.

Gross L, Birnbaum LS (2017) Regulating toxic chemicals for public and environmental health. PLoS Biol 15(12): e2004814. https://doi.org/10.1371/journal.pbio.2004814

Kortenkamp and Faust 2018 Regulate to reduce chemical mixture risk. Science. Vol 361 Issue 6399. p.224-226

Norouzitallab et al 2019. Can epigenetics translate environmental cues into phenotypes? Science of the Total Environment. 647:1281-1293

Roth TL. (2012) Epigenetics of neurobiology and behavior during development and adulthood. Dev Psychobiol 2012; 54: 590–97.

Schuster A., Skinner M., and Yan W. (2016) Ancestral vinclozolin exposure alters the epigenetic transgenerational inheritance of sperm small noncoding RNAs. Environmental Epigenetics. 2016; 2(1): dvw001.

Skinner. M. (2014) Endocrine Disruptor Induction of Epigenetic Transgenerational Inheritance of Disease. Mol Cell Endocrinol. 2014 Dec; 398(0): 4–12. 2014 Jul 31. doi:  10.1016/j.mce.2014.07.019 PMCID: PMC4262585

Trasande et al 2015. Estimating Burden and Disease Costs of Exposure to Endocrine-Disrupting Chemicals in the European Union. J Clin Endocrinol Metab, April 2015, 100(4):1245–1255doi: 10.1210/jc.2014-4324 http://press.endocrine.org/doi/pdf/10.1210/jc.2014-4324

Trasande et al 2016. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union: an updated analysis. Andrology. 2016 Jul;4(4):565-72. doi: 10.1111/andr.12178. Epub 2016

Trasande L. 2019 Sicker, Fatter, Poorer: The Urgent Threat of Hormone-Disrupting Chemicals to Our Health and Future . . . and What We Can Do About It. Houghton Mifflin Harcourt.

Attina T, Hauser R., Sathyanarayana S., Hunt P., Bourguignon J.P., Myers J.P. , Digangi J., Zoeller R.T., Trasande L.. Exposure to endocrine-disrupting chemicals in the USA: a population-based disease burden and cost analysis. The Lancet Diabetes & Endocrinology, 2016 DOI: 10.1016/S2213-8587(16)30275-3

UN Human Rights Council. Report of the Special Rapporteur on the implications for human rights of the environmentally sound management and disposal of hazardous substances and wastes on his mission to Germany* 14 September 2016. A/HRC/33/41/Add.2

World Health Organization, United Nations Environment Programme, Inter-Organization Programme for the Sound Management of Chemicals, Bergman, Åke, Heindel, Jerrold J. et al. (‎2013)‎. State of the science of endocrine disrupting chemicals 2012. World Health Organization.

Waterland, R.A. and Jirtle R.L. (2003) Transposable Elements: Targets for Early Nutritional Effects on Epigenetic Gene Regulation. Molecular and Cellular Biology 2003; 23(15): 5293–5300.

WHO. Children are not little adults. Children's Health & the Environment, WHO Training Package for the Health Sector World Health Organization July 2008

Zhang, X., and Ho, S.M. (2011) Epigenetics meets endocrinology. Journal of Molecular Endocrinology. 46(1): R11–R32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4071959/pdf/nihms-601840.pdf

 

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