Epigenetics refers to how and when genes are turned on and off. Epigenetics have a strong influence on normal development and growth, and disease exists when epigenetics become unregulated. The diet we eat and the environment we live in can cause changes in our epigenetics that may switch our genes on or off. A healthy diet and clean environment improves our epigenetic processes. Botanical and nutritional supplements are used to switch good genes on and bad genes off. In Down Syndrome, silencing over expressed genes at a young age can make people with DS healthier later in life.


At the forefront of biomedical research today is the study of Epigenetics [1]. Epigenetic events control normal and abnormal cellular processes associated with diseases. Knowledge of Epigenetics has witnessed a recent explosion since the mapping of the Human Genome in 2000 [2]. Epigenetic influences have not been well investigated in relation to Down Syndrome (DS) [3].

What are Epigenetics?

Epigenetics is the study of biological mechanisms that switch genes on and off. Epigenetics includes all the processes involved in creating instructions for a cell to function efficiently. Epigenetic changes appear to be stable, but they can be influenced by many things such as physiology, pathology and environment [4, 5, 6].

DNA methylation is the best known epigenetic influence, controlling the expression of genes and construction of the cell nucleus [7].  DNA methylation patterns are carried out by three DNA methyltransferases, DNMT1, DNMT3a and DNMT3b which transfer methyl groups from SAMe to DNA. Histone modification and micro-RNA’s are considered other well studied epigenetic mechanisms [8].

Aging is an epigenetic process associated with both hypo and hyper DNA methylation [4, 9] and is altered by a combination of genetic and environmental influences [10].

Environmental factors that influence epigenetics are classified into four groups: diet and nutrition, home or workplace, pharmacological treatments (drugs) and unhealthy habits such as smoking and drinking alcohol [8].

Diet includes intake of folate for the remethylation of homocysteine [11, 12] methionine for the formation of SAMe [8]. Supplementation with choline during pregnancy and breastfeeding increased attentiveness in DS mice [13]. Dietary Polyphenols such as EGCg from Green Tea and nutrients like selenium influence epigenetics through their prevention of cancer [14, 15]. Other natural substances such as butyrate in cheese, disulphide in garlic and sulphurophane in broccoli disrupt uncontrolled cell cycle progression and encourage selective cell death (apoptosis) which are epigenetic functions [16, 17].

The home and workplace can affect our epigenetics exposing us to many environmental factors such as chemicals and xenobiotics found in water. Inhalation of asbestos alters methylation function [18]. Environmental pollutants such as chromium [19], cadmium [20] and nickel [21] reduce methylation levels by inhibiting DNA methyltransferases and nickel also reduces histone function, repressing genes [22].

Bisphenol A found in plastic containers [23], and the fungicide vinclozolin [24] used in vineyards are endocrine disruptors and have been linked to alteration of DNA methylation, developmental disorders and tumours. Alcohol, tobacco and drug use alter epigenetics by changing DNA methylation. It isn’t known whether these epigenetic changes are stable over time [8].


Epigenetics and Cognition

Until now, most DS studies have focused on genetics, despite increasing evidence that epigenetics  plays a big role in learning and memory [3]. Few studies have investigated epigenetic therapy in DS [3]. Pharmaceutical treatment has not been successful in reducing cognitive decline in DS [25, 26] and epigenetics offer potentially important new avenues of research.

Epigenetics play a role in regulating gene expression [27] and may have an impact on the development of cognitive decline in DS. Epigenetic marks such as histone modifications and DNA methylation are reversible and offer enormous potential to reduce genetic imbalances [3].

Evidence illustrating the role of epigenetics in brain plasticity, learning and memory is increasing [3]. Memory formation relies on decreased DNA methylation of memory promoting genes and increased DNA methylation of memory suppressor genes [28, 29]. In addition, histones have been implicated in rescuing poor memory and promoting memory formation and synaptic plasticity [30].

“Cognitive epigenetics” is an emerging field of research examining the effect of epigenetics on synaptic plasticity, learning and memory [28] Animal models and human intellectual disability studies clearly demonstrate that epigenetics is essential for learning and memory [28].

MiRNA’s also play a role in neurodevelopment, synaptic plasticity, learning and memory [31, 32]. Formation of long-term memory is dependent on miRNA’s gene transcription and translation in the brain. MiRNA’s and IncRNA’s can regulate gene transcription by affecting epigenetic marks through stimulation of enzymes, and from their direct effect on transcription and translation [31, 32].

Epigenetics and T21

In 1959 Le Jeune et al. [33] demonstrated that DS was caused by a triplication of chromosome 21 (HSA21). In over 95% of cases this is a trisomy of the whole chromosome due to the failure of one pair of chromosomes to separate [34, 35] .

In 2000 the complete DNA sequence of HSA21 was revealed following completion of the Human Genome Project [36]. Investigation of over expressed genes and their effect on learning and memory has been carried out since then. Yet it remains difficult to explain widespread variability among the DS population, despite an increased understanding of underlying genetics [37, 38]. Theoretically, the triplication of HSA21 would lead to a 1.5 fold increase in gene transcription. Gene expression studies show different results. Examination of HSA21 gene expression in DS lymphocytes revealed that only 22% were expressed close to the 1.5 fold increase, compared to controls. Amplified expression was observed in 7%, significantly lower expression was observed in 56% and highly variable expression was observed in 15% [39]. The mouse model of DS, Ts65Dn obtained similar results, demonstrating that a deviation in the theoretical 1.5 fold increase in gene expression exists [34, 40, 41]. In a study by Lyle et al. [41] no more than 37% of genes in Ts65Dn reached the theoretical 1.5 expression level.

Epigenetics, Alzheimer’s disease and T21

The increased risk of developing Alzheimer’s disease (AD) in DS compared to the non-DS population is considered to be caused by triplication of the amyloid precursor protein (APP) gene on HSA21, forming high levels of amyloid-B plaque [42]. Despite the fact that 95% of DS individuals have a whole-chromosome trisomy, enormous variety exists in the type and severity of presentation [43, 54]. As an example, there is enormous variability in the onset of dementia symptoms in DS individuals. Despite the formation of AB plaques and neuropathology in midlife, 30-50% of DS individuals don’t develop dementia [44, 42, 45, 46].

Focusing on the effects of an over expressed APP on HSA21 is too limiting to explain the differences in variability of AD in DS. Obviously, other factors determine why someone develops symptoms of AD in DS or not, despite the presence of plaque in the brain. Its not well understood which factors are contributing the most to AD in DS. However, its likely that the presence or absence of dementia is the result of differences in the expression levels of these intervening factors. Epigenetic factors are likely to be the key to development of AD in DS and should be examined closely for their therapeutic benefits.

Various over expressed genes on HSA21 have downstream epigenetic effects which play a role in AD progression. DYRK1 phosphorylates APP [47] and tau proteins at several sites affecting AD pathology [48]. Expression of MiRNA’s are altered in the AD brain potentially related to miRNA-125b2 which is over expressed in DS [49].

Epigenetic alterations exist in the general population of people with AD, according to emerging research.  DNA methylation, histone acetylation and methylation are disturbed in AD [50]. and are likely to be altered in people with DS as well.

Therapies for Cognitive Decline

Clinical trials (U.S. National Institutes of Health, 2013) [51] aimed at improving poor memory and learning and targeting early onset AD in DS have not produced promising results. Various pharmacological treatments to improve cognition in DS have been tested, and despite positive effects [52], none have been approved for use.

In addition, clinical drug trials for AD in the typical population have been unsuccessful. The USFDA has approved the use of donepezil – a cholinesterase inhibitor, for short term relief of cognitive improvement without addressing neurodegeneration [53].

Understanding the important role that epigenetics play in cognitive development, the investigation of new therapies is essential. Epigenetic alterations contribute to neurodegeneration and are likely to effect cognitive decline in DS. Epigenetic marks are reversible, unlike triplication of HSA21, and should be pursued for their positive effect on DS pathology. Phytotherapy and nutrients which inhibit epigenetic enzymes offer a promising alternative to drugs and should be explored further.

Targeted Intervention

Innovative new approaches to treating genes and pathways underlying DS pathology are being examined. Targeting epigenetic enzymes to silence individual genes such as DYRK1 and APP, are altering their role in DS pathology. Epigenetic changes at the site of the target gene produce long term changes in gene expression, either stimulating or suppressing their expression. This opens new avenues to reducing cognitive decline in DS. Certain HSA21 genes have already been identified and targeted due to their over expression and effect on the genome. In future, other genes not sitting on HSA21, which affect DS pathology should be investigated including groups and subgroups with and without AD and groups of different ages.


The role of cognitive epigenetics in memory and learning is in its infancy, despite growing research in intellectual disability which predicts its role is crucial. No preventive pharmaceutical treatment is currently available to address early onset AD or cognitive decline, despite various clinical trials.

Triplication of HSA21 was thought to increase gene expression 1.5 fold However, recent studies reveal a deviation from this, varying the characteristics of DS individuals. Gene characterisation has been the focus of research, while underlying epigenetic mechanisms have been neglected. It is emerging now that by regulating gene expression, epigenetics play a crucial role in cognitive decline associated with DS.

Epigenetic processes are disturbed in DS due to the over expressed HSA21 genes and their products. Due to their regulation of genome function epigenetics affect cognitive decline in DS. This includes DNA methylation, histone modification and chromatin remodelling through miRNA’s and incRNA’s.

Prevention and improvement of the symptoms of DS, particularly cognition, are possible with epigenetic approaches to treatment. Targeted Intervention which actively modulates gene expression by targeting specific epigenetic enzymes holds the most promise. Down regulating over expressed HSA21 genes changes their physiological impact to avoid cognitive decline in DS.

Epigenetics are clearly involved in intellectual disabilities. Despite limited studies of epigenetic in DS, disturbances are indicated due to over expression of HSA21 genes. Future research needs to identify these epigenetic marks in DS compared to the typical population in order to continue to Target Nutritional Intervention to down regulate genes and over write epigenetic marks.

by Gabi Giacomin

  1. Herceg Z1, Ushijima T. Introduction: epigenetics and cancer. Adv Genet. 2010;70:1-23.
  2. Kussmann M1, Krause L, Siffert W. Nutrigenomics: where are we with genetic and epigenetic markers for disposition and susceptibility? Nutr Rev. 2010 Nov;68 Suppl 1:S38-47.
  3. Dekkera A D,De Deyna P P, Rotsc M G, Epigenetics: The neglected key to minimize learning and memory deficits in Down syndrome. Neuroscience & Biobehavioral Reviews, Volume 45, September 2014, Pages 72–84
  4. Issa JP. Age-related epigenetic changes and the immune system. Clin Immunol 109: 103–108, 2003.
  5. Romieu P, Host L, Gobaille S, Sandner G, Aunis D, Zwiller J. Histone deacetylase inhibitors decrease cocaine but not sucrose self-administra- tion in rats. J Neurosci 28: 9342–9348, 2008.
  6. Whitelaw NC, Whitelaw E. How lifetimes shape epigenotype within and across generations. Hum Mol Genet 15, Spec No 2: R131–137, 2006.
  7. Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. N Engl J Med 349: 2042–2054, 2003.
  8. Aguilera O, FernándezAlberto Muñoz A, and Fragg M F. Epigenetics and environment: a complex relationship. J Appl Physiol 109: 243–251, 2010. First published April 8, 2010;
  9. Oakes CC, Smiraglia DJ, Plass C, Trasler JM, Robaire B. Aging results in hypermethylation of ribosomal DNA in sperm and liver of male rats. Proc Natl Acad Sci U S A 100: 1775–1780, 2003.
  10. Fraga MF. Genetic and epigenetic regulation of aging. Curr Opin Immunol 21: 446 –453, 2009
  11. Keyes MK, Jang H, Mason JB, Liu Z, Crott JW, Smith DE, Friso S, Choi SW. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. J Nutr 137: 1713–1717, 2007
  12. Kotsopoulos J, Sohn KJ, Kim YI. Postweaning dietary folate deficiency provided through childhood to puberty permanently increases genomic DNA methylation in adult rat liver. J Nutr 138: 703–709, 2008.
  13. Moon, J., Chen, M., Gandhy, S.U., Strawderman, M., Levitsky, D.A., Maclean, K.N., Strupp, B.J., 2010. Perinatal choline supplementation improves cognitive functioning and emotion regulation in the Ts65Dn mouse model of Down syndrome. Behav. Neurosci. 124, 346–361.
  14. Fang M, Chen D, Yang CS. Dietary polyphenols may affect DNA
    methylation. J Nutr 137: 223S–228S, 2007.
  15. Xiang N, Zhao R, Song G, Zhong W. Selenite reactivates silenced genes by modifying DNA methylation and histones in prostate cancer cells. Carcinogenesis 29: 2175–2181, 2008
  16. Calvanese V, Lara E, Kahn A, Fraga MF. The role of epigenetics in aging and age-related diseases. Ageing Res Rev 8: 268–276, 2009.
  17. Dashwood RH, Ho E. Dietary histone deacetylase inhibitors: from cells to mice to man. Semin Cancer Biol 17: 363–369, 2007
  18. Christensen BC, Houseman EA, Marsit CJ, Zheng S, Wrensch MR, Wiemels JL, Nelson HH, Karagas MR, Padbury JF, Bueno R, Sugarbaker DJ, Yeh RF, Wiencke JK, Kelsey KT. Aging and envi- ronmental exposures alter tissue-specific DNA methylation dependent upon CpG island context. PLoS Genet 5: e1000602, 2009.
  19. Shiao YH, Crawford EB, Anderson LM, Patel P, Ko K. Allele- specific germ cell epimutation in the spacer promoter of the 45S ribo- somal RNA gene after Cr(III) exposure. Toxicol Appl Pharmacol 205: 290–296, 2005.
  20. Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286: 355–365, 2003.
  21. Salnikow K, Costa M. Epigenetic mechanisms of nickel carcinogenesis. J Environ Pathol Toxicol Oncol 19: 307–318, 2000.
  22. Chen H, Ke Q, Kluz T, Yan Y, Costa M. Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol Cell Biol 26: 3728 –3737, 2006.
  23. Maffini MV, Rubin BS, Sonnenschein C, Soto AM. Endocrine disrup- tors and reproductive health: the case of bisphenol-A. Mol Cell Endo- crinol 254–255: 179–186, 2006.
  24. Anway MD, Leathers C, Skinner MK. Endocrine disruptor vinclozolin induced epigenetic transgenerational adult-onset disease. Endocrinology 147: 5515–5523, 2006
  25. Braudeau J, Dauphinot L, Duchon A, Loistron A, Dodd RH, Herault Y, Delatour B. Potier MC. Chronic treatment with a promnesiant GABA-A alpha5-selective inverse agonist increases immediate early genes expression during memory processing in mice and rectifies their expression levels in a Down syndrome mouse model Adv. Pharmacol. Sci., 2011 (2011), p. 153218
  26. Underwood, E., 2014. Can Down syndrome be treated? Science 343, 964–967.
  27. Berger S L, Kouzarides T, Shiekhattar R, Shilatifard A. An operational definition of epigenetics Genes Dev., 23 (2009), pp. 781–783
  28. Day J J, Sweatt J D. DNA methylation and memory formation Nat. Neurosci., 13 (2010), pp. 1319–1323
  29. Weng Y L, An R, Shin J, Song H, Ming G L. DNA modifications and neurological disorders Neurotherapeutics, 10 (2013), pp. 556–567
  30. Graff J, Tsai L H. Histone acetylation: molecular mnemonics on the chromatin Nat. Rev. Neurosci., 14 (2013), pp. 97–111
  31. Della Ragione F, Gagliardi M, D’Esposito M, Matarazzo M R Non-coding RNAs in chromatin disease involving neurological defects Front. Cell. Neurosci., 8 (2014), p. 54
  32. Saab B J, Mansuy I M. Neuroepigenetics of memory formation and impairment: the role of microRNAs Neuropharmacology, 80C (2014), pp. 61–69
  33. Lejeune J, Turpin R, Gautier M. Mongolism; a chromosomal disease (trisomy) Bull. Acad. Natl. Med., 143 (1959), pp. 256–265
  34. Antonarakis S E, Lyle R, Dermitzakis E T, Reymond A, S. Deutsch Chromosome 21 and down syndrome: from genomics to pathophysiology Nat. Rev. Genet., 5 (2004), pp. 725–738
  35. Lubec G, Engidawork E. The brain in Down syndrome (TRISOMY 21) J. Neurol., 249 (2002), pp. 1347–1356
  36. Hattori M, A. Fujiyama, T.D. Taylor, H. Watanabe, T. Yada, H.S. Park, A. Toyoda, K. Ishii, Y. Totoki, D.K. Choi, Y. Groner, E. Soeda, M. Ohki, T. Takagi, Y. Sakaki, S. Taudien, K. Blechschmidt, A. Polley, U. Menzel, J. Delabar, K. Kumpf, R. Lehmann, D. Patterson, K. Reichwald, A. Rump, M. Schillhabel, A. Schudy, W. Zimmermann, A. Rosenthal, J. Kudoh, K. Schibuya, K. Kawasaki, S. Asakawa, A. Shintani, T. Sasaki, K. Nagamine, S. Mitsuyama, S.E. Antonarakis, S. Minoshima, N. Shimizu, G. Nordsiek, K. Hornischer, P. Brant, M. Scharfe, O. Schon, A. Desario, J. Reichelt, G. Kauer, H. Blocker, J. Ramser, A. Beck, S. Klages, S. Hennig, L. Riesselmann, E. Dagand, T. Haaf, S. Wehrmeyer, K. Borzym, K. Gardiner, D. Nizetic, F. Francis, H. Lehrach, R. Reinhardt, M.L. Yaspo, Chromosome 21 mapping and sequencing consortium The DNA sequence of human chromosome 21 Nature, 405 (2000), pp. 311–319
  37. Jiang J, Y. Jing, G.J. Cost, J.C. Chiang, H.J. Kolpa, A.M. Cotton, D.M. Carone, B.R. Carone, D.A. Shivak, D.Y. Guschin, J.R. Pearl, E.J. Rebar, M. Byron, P.D. Gregory, C.J. Brown, F.D. Urnov, L.L. Hall, J.B. Lawrence Translating dosage compensation to trisomy 21 Nature, 500 (2013), pp. 296–300
  38. Prandini P, S. Deutsch, R. Lyle, M. Gagnebin, C. Delucinge Vivier, M. Delorenzi, C. Gehrig, P. Descombes, S. Sherman, F. Dagna Bricarelli, C. Baldo, A. Novelli, B. Dallapiccola, S.E. Antonarakis Natural gene-expression variation in Down syndrome modulates the outcome of gene-dosage imbalance Am. J. Hum. Genet., 81 (2007), pp. 252–263E.
  39. Ait Yahya-Graison, J. Aubert, L. Dauphinot, I. Rivals, M. Prieur, G. Golfier, J. Rossier, L. Personnaz, N. Creau, H. Blehaut, S. Robin, J.M. Delabar, M.C. PotierClassification of human chromosome 21 gene-expression variations in Down syndrome: impact on disease phenotypes Am. J. Hum. Genet., 81 (2007), pp. 475–491
  40. Kahlem P, M. Sultan, R. Herwig, M. Steinfath, D. Balzereit, B. Eppens, N.G. Saran, M.T. Pletcher, S.T. South, G. Stetten, H. Lehrach, R.H. Reeves, M.L. Yaspo Transcript level alterations reflect gene dosage effects across multiple tissues in a mouse model of down syndrome Genome Res., 14 (2004), pp. 1258–1267
  41. Lyle R, C. Gehrig, C. Neergaard-Henrichsen, S. Deutsch, S.E. Antonarakis Gene expression from the aneuploid chromosome in a trisomy mouse model of down syndrome Genome Res., 14 (2004), pp. 1268–1274
  42. Ness S, M. Rafii, P. Aisen, M. Krams, W. Silverman, H. Manji Down’s syndrome and Alzheimer’s disease: towards secondary prevention Nat. Rev. Drug Discov., 11 (2012), pp. 655–656
  43. Roper R J, R.H. Reeves Understanding the basis for Down syndrome phenotypes PLoS Genet., 2 (2006), p. e50
  44. Lott I T, M. Dierssen Cognitive deficits and associated neurological complications in individuals with Down’s syndrome Lancet Neurol., 9 (2010), pp. 623–633
  45. Wilcock D M. Neuroinflammation in the aging down syndrome brain; lessons from Alzheimer’s disease Curr. Gerontol. Geriatr. Res., 2012 (2012), p. 170276
  46. Zigman W B, I.T. Lott Alzheimer’s disease in Down syndrome: neurobiology and risk Ment. Retard. Dev. Disabil. Res. Rev., 13 (2007), pp. 237–246
  47. Ryoo S R, H.J. Cho, H.W. Lee, H.K. Jeong, C. Radnaabazar, Y.S. Kim, M.J. Kim, M.Y. Son, H. Seo, S.H. Chung, W.J. Song Dual-specificity tyrosine(Y)-phosphorylation regulated kinase 1A-mediated phosphorylation of amyloid precursor protein: evidence for a functional link between Down syndrome and Alzheimer’s disease J. Neurochem., 104 (2008), pp. 1333–1344
  48. Liu F, Z. Liang, J. Wegiel, Y.W. Hwang, K. Iqbal, I. Grundke-Iqbal, N. Ramakrishna, C.X. Gong Overexpression of Dyrk1A contributes to neurofibrillary degeneration in Down syndrome FASEB J., 22 (2008), pp. 3224–3233
  49. Lukiw W J. Micro-RNA speciation in fetal, adult and Alzheimer’s disease hippocampus Neuroreport, 18 (2007), pp. 297–300
  50. Veerappan C S, S. Sleiman, G. Coppola Epigenetics of Alzheimer’s disease and frontotemporal dementia Neurotherapeutics, 10 (2013), pp. 709–721
  51. U.S. National Institutes of Health ClinicalTrials.gov (2013)
  52. Wiseman F K, K.A. Alford, V.L. Tybulewicz, E.M. Fisher Down syndrome-recent progress and future prospects Hum. Mol. Genet., 18 (2009), pp. R75–R83
  53. Mangialasche F, A. Solomon, B. Winblad, P. Mecocci, M. Kivipelto Alzheimer’s disease: clinical trials and drug development Lancet Neurol., 9 (2010), pp. 702–716
  54. Mentis A.F., Epigenomic engineering for Down syndrome. Neuroscience and Biobehavioral Reviews 71 (2016) 323–327

Share This: