Why epigenetics is important

This subtle molecular difference may underlie the the differential rates of psychosis seen in deletion and mUPD PWS sub-types. In addition to the main phenotypic characteristics, both AS and PWS display a high incidence of neuropsychiatric abnormalities.

Individuals with PWS in particular are prone to an affective disorder, including mood instability, non-psychotic depression and psychosis. These data allow us to start assigning specific gene s to particular parts of the phenotype; for instance, the predicted over-dosage of maternally expressed UBE3A and ATP10C gene products due to the presence of two maternal copies in the mUPDs suggests that these gene products are important in the aetiology of psychosis in PWS.

In addition to the specific examples provided by these two syndromes, more general imprinted gene effects if not actual genes have been assigned to various psychiatric illness including Tourettes syndrome, Bipolar disorder, schizophrenia and autism. In addition to physical changes in the DNA encoding imprinted genes mutation, deletion, duplication of the DNA sequence , disruption of the epigenetic regulation itself can also result in abnormalities.

A striking example of this is when there is a mutation in one of the genes encoding part of the regulatory cascade, as occurs in Rett syndrome. It is a severe, progressive neurodevelopmental syndrome, affecting only girls the mutation is lethal in males , which demonstrates a number of overlapping clinical features with autism and AS.

This latter observation has been strengthened by recent molecular analysis of the role of methyl CpG binding protein 2, the product encoded by MeCP2. MeCP2 is a nuclear protein that binds specifically to methylated DNA, of crucial importance in the epigenetic control of imprinted expression. This possibly also results in changes in the 3-D conformation of the chromatin, reducing the access of the expression machinery to the DNA sequence.

Given these molecular links, and the overlap in clinical features between AS, Rett and autism, we can begin to ascribe aspects of brain abnormalities to genes and underlying neurobiology, in this case for instance, synaptic dysfunction. A number of animal studies have established that in vitro culture of early stage embryos disrupts the normal developmentally programmed epigenetic processes.

These can have pronounced phenotypic effects, particularly in ruminants, 23 and may provide an explanation for the foetal over-growth and other problems seen in cloned animals. It is against this background that attention has recently turned to examining the consequences of assisted reproductive technologies ART on imprinted-gene-related disorders. There is an accumulating body of evidence suggesting that this is indeed the case, although it must be stressed that as many imprinted gene disorders are in themselves quite rare, the absolute risk is extremely low.

Furthermore, this demonstrates quite nicely the fact that unlike the far more stable DNA code, the information provided by the epigenome is less fixed.

Although many epigenetic modifications are developmentally determined, there is also an inherent lability in some, as has been demonstrated by the effects of ART, described above, and also of toxins and environmental insults. In monozygotic twins, where the DNA code is identical, the epigenome of twins diverged with age, 31 suggesting that this may be a molecular mechanism by which differing life experiences are encoded.

These data set up the possibility that epigenetic marks may have evolved as an additional molecular response mechanism, speeding up the process of adaptation to a changing or less predictable environment.

A good example of this is provided by the epigenetic inheritance of maternal behaviours. Variations in care given to pups by female rats has long-lasting consequences for the development of those offspring, including affects on cognition and response to stress.

These variations in maternal care are transmitted across generations, such that low licking and grooming LG mothers beget low LG mothers. Fascinatingly, this inheritance of maternal care is non-genomic. The opposite effect is seen with individuals raised by low LG mothers. These molecular changes are probably not heritable themselves, rather the behaviour of the mother sets up key molecular changes that last into adulthood affecting subsequent brain function.

But how are we to understand this code? There are upwards of 35 genes in people, on top of this there are eight core histones, which may be modified in at least 25 different ways, each of which could theoretically encode differing information. There are moves to decipher this code, 37 but in the first instance in order to establish the idea is indeed valid, it may be necessary to centre the epigenetic decoding on a limited set of genes.

One way of doing this is by focusing on gene variants that give rise to disease. A number of gene candidates have now been identified that pre-dispose individuals to neuropsychiatric disorders. Recently it has been shown, not unexpectedly, that these do not automatically result in a disease, but that life events in combination with certain gene variants give a far higher likelihood of developing the disorder.

For instance, a polymorphic variant of the gene encoding the monoamine oxidase A MAO-A that results in higher expression of this neurotransmitter metabolizing enzyme protects individuals from developing violent tendencies after experiencing maltreatment as children. Thus far studies of these kinds are few and far between. For instance, one hypothetical scenario could be that experiencing maltreatment results in increased DNA-methylation at the MAO-A gene, therefore decreasing its expression.

Those individuals with a high-expression genetic polymorphism are spared any effects, but those with the low-expression variant have MAO-A levels that dip below a key threshold, resulting in a tendency to be violent in later life. Nevertheless, at present these ideas remain untested and are purely theoretical. In this review we have begun to address the contribution of epigenetic mechanisms to brain function, and consequently dysfunction in the form of neuropsychiatric disorders.

Interestingly, a recent study identified differentially methylated regions in post-mitotic cells as shown in monocyte cultures differentiating to dendritic cell or macrophage populations [ 50 ].

Transmission of epigenetic and genetic states for example, DNA methylation vary considerably, with an error rate of 1 in 10 6 DNA sequence as compared with 1 in 10 3 DNA modification [ 51 ]. Consequently, epigenetic signatures and marks differ fundamentally from genetic lesions by showing a stochastic manifestation and often incomplete distribution, and are in principle at least partially reversible.

Although much still needs to be learned in terms of biological and clinical significance of the reversible nature of these epigenetic modifications, it does make the chromatin-modifying enzymes possible therapeutic targets as discussed in some detail further below. Genome-wide association studies GWASs , for example, have provided a wealth of possible genetic factors contributing to the phenotypic diversity of syndromes such as RA and ankylosing spondylitis [ 56 , 57 ].

Genes identified by searches for common genetic variants associated with disease have been highly productive in both RA and ankylosing spondylitis, and the effect of targeting the products of such contributory genes may be disproportionately greater than the apparent contribution to syndrome susceptibility.

Furthermore, gene associations have thus far failed to explain the heterogeneity of clinical features and response to targeted therapies across patient subgroups. This concept of missing heritability might be at least in part explained by several mechanisms such as unmapped common variants, rare variants, gene-gene interaction or, not unlikely, epigenetic mechanisms.

Many of the regions identified in GWAS do not coincide with coding regions, however, but overlap with functional regulatory regions such as enhancers or transcription start sites identified in the ENCODE project [ 7 , 9 ]. In addition, risk loci such as the MHC cluster could be targeted by epigenetic modification such as DNA methylation [ 25 ].

Epigenetics might also link environmental risk factors with genetic variation. Importantly, the epigenome itself is subject to environmental influences, as documented in multiple instances [ 58 — 61 ], and thus could act in concert with genetic variation to explain phenotypic variation and plasticity [ 62 , 63 ]. Among chronic inflammatory diseases, RA has the highest prevalence in the western world and is a chronic and progressive inflammatory disease.

Of note, a correlation between smoking and hypomethylation of a CpG motif in the IL-6 promoter and resulting increased cytokine levels was established in a recent study among RA and chronic periodontitis patients [ 65 ].

This correlation indicates that a causal environmental disease trigger could indeed lead to a change in cytokine profile, although the connecting epigenetic mechanism in this relationship needs to be further defined. The pathogenesis of disease in RA is attributed to the production of proinflammatory cytokines from activated cells that infiltrate the synovial tissues from the blood T cells, macrophages, plasma cells together with resident cell types fibroblasts and endothelium.

Multiple studies addressing chromatin and DNA modifications in several autoimmune diseases for reviews see [ 66 — 68 ] have clearly shown that tissue-specific epigenetic modifications play a role in autoimmune disease.

In RA peripheral blood mononuclear cells, demethylation of a single CpG in the IL-6 promoter region increased the production of this proinflammatory cytokine [ 71 ]. Furthermore, RA synovial fibroblasts-that is, the effector cells of joint and bone destruction in RA-present an intrinsic aggressive behaviour even in the absence of cells of the immune system or cytokines.

Interestingly, epigenetic inhibitor therapy appears to have therapeutic potential in suppressing proliferation and aggressive phenotype of synovial fibroblasts [ 77 — 79 ].

The effect of inhibition of DNA methyltransferases by 5-aza-deoxycytidine, procainamide or hydralazine on T-cell function, and the subsequent development of systemic lupus erythematosis, underscores the importance of epigenetic modifications in this case, DNA methylation in autoimmunity [ 80 ]. Furthermore, the histone components of nucleosomes and anti-nucleosome antibody-nucleosome adducts have both been implicated as severe immunostimulatory factors [ 81 , 82 ].

As demonstrated by the examples given above, the characterisation of epigenomic modifications focusing on post-translational histone modifications has started to make significant advances in both the adaptive immune system in T-cell differentiation and the innate immune system in, for example, the regulation of TNF gene expression in macrophages.

As discussed above, there are certainly good indicators that epigenetic mechanisms do play a role in pathogenesis and might even be targets for therapeutic intervention cf. Table 2 within the musculoskeletal disease arena, which includes inflammatory conditions such as RA as well as degenerative or malignant diseases such as osteoarthritis or bone cancers.

The target classes identified in these studies comprise well-established HDAC including clinically used inhibitors or miRNAs, as well as novel targets such as bromodomains, histone methyltransferases or histone demethylases. Epigenetic target discovery in chronic inflammatory diseases is expected to mirror the efforts currently invested in epigenetic drug development in oncology.

This hypothesis is highlighted by the recent discovery that selective and potent inhibitors can be developed against a class of histone 3 lysine 27 H3K27 demethylase enzymes, which inhibit proinflammatory cytokine production in lipopolysaccharide-stimulated primary macrophages from healthy individuals or RA patients [ 31 ].

The inhibitor study is the first of its kind, and a proof of concept that modulation of chromatin modification systems is of potential therapeutic benefit in controlling proinflammatory mechanisms. In addition, the lipopolysaccharide response in macrophages was recently discovered to require the H3K4 methyltransferase Kmt2b [ 83 ], pointing to novel opportunities to modulate inflammatory responses.

The compelling functional impact of epigenomic modulation in the immune system has also recently been demonstrated through the remarkable pharmacology seen with bromodomain and extraterminal bromodomain inhibitor treatment in mouse models of bacterial sepsis [ 84 ]. Inhibitors of this bromodomain and extra-terminal class have been shown to critically regulate effects of MYC and pTEFb transcriptional complexes [ 84 — 86 ]. Although some discrepancies remain with regards to the specificity of the proinflammatory profiles that require further investigation [ 87 ], the results clearly support the notion that bromodomain proteins are key regulators of the inflammatory response and constitute targets for anti-inflammatory target discovery [ 87 ].

Consequently, these data also extend the disease applications of anti-inflammatory bromodomain inhibitors into metabolic disorders such as obesity and insulin resistance that have a strong inflammatory component. In addition, HDAC inhibitors for example, MS, Trichostatin A have shown therapeutic activity in inhibition of synovial fibroblast proliferation [ 77 , 78 ] as well as in stress-induced osteoarthritis models-for example, by inhibiting cyclic tensile strain-induced expression of RUNX-2 and ADAMTS-5 via the inhibition of mitogen-activated protein kinase pathway activation in human chondrocytes [ 89 , 90 ].

The rise of epigenetics highlights the maturation of an area, created half a century ago, which is still associated with a somewhat blurred definition. Despite this uncertainty, epigenetics is now a dynamic discipline, driving new technological advances as well as challenging and revising traditional paradigms of biology.

Through epigenetics the classic genetic works are now seen in different ways, and combined they help to understand the roles and interplay of DNA, RNA, proteins, and environment in inheritance and disease aetiology. The epigenetics field is anticipated to contribute to understanding of the complexities of genetic regulation, cellular differentiation, embryology, aging and disease but also to allow one to systematically explore novel therapeutic avenues, ultimately leading to personalised medicine.

For the foreseeable future, epigenetics will contribute in at least two ways to the understanding of musculoskeletal disease. First, the systematic mapping of functional chromatin elements in combination with GWAS outputs has generated a rich set of hypotheses to be further tested in order to identify relevant pathways, and to understand phenotypic variation and plasticity in human disease.

Secondly, epigenetic chemical biology and drug discovery, although in its infancy, has already resulted in identification of novel, possible targets in, for example, inflammatory disease.

Although much has to be learned in terms of mechanisms, therapeutic utility, efficacy and safety of drugs targeting epigenetic modifiers in inflammation, these novel approaches hold promise for the future of drug discovery in inflammatory and musculoskeletal disease.

Google Scholar. Bird A: Perceptions of epigenetics. Ptashne M: On the use of the word 'epigenetic'. Curr Biol. Genes Dev. Nat Rev Genet. Feinberg AP: Epigenomics reveals a functional genome anatomy and a new approach to common disease. Nat Biotechnol. After quitting smoking, former smokers can begin to have increased DNA methylation at this gene. Eventually, they can reach levels similar to those of non-smokers. In some cases, this can happen in under a year, but the length of time depends on how long and how much someone smoked before quitting 2.

Mycobacterium tuberculosis causes tuberculosis. Colorectal cancers have increased methylation at the SEPT9 gene. When used with other diagnostic screening tests, these epigenetic based tests can help find cancer early 5 6. People whose mothers were pregnant with them during the famine were more likely to develop certain diseases such as heart disease, schizophrenia, and type 2 diabetes 7. Around 60 years after the famine, researchers looked at methylation levels in people whose mothers were pregnant with them during the famine.

These people had increased methylation at some genes and decreased methylation at other genes compared with their siblings who were not exposed to famine before their birth 8 9 These differences in methylation could help explain why these people had an increased likelihood for certain diseases later in life 7 10 11 Skip directly to site content Skip directly to page options Skip directly to A-Z link. Section Navigation. Facebook Twitter LinkedIn Syndicate. What is Epigenetics?

Minus Related Pages. How Can Your Epigenetics Change? Epigenetics and Development Epigenetic changes begin before you are born. All your cells have the same genes but look and act differently. As you grow and develop, epigenetics helps determine which function a cell will have, for example, whether it will become a heart cell, nerve cell, or skin cell.

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