So what does cancer and epigenetics have to do with each other? Basically, cancer-causing changes are caused by DNA methylation and histone modification, two mechanisms of epigenetics (30). Various genetic modifications, studied by epigenetics, have been linked to cancer (30). This lead to the analysis of the sites, which led up to the indication of carcinogenesis. Both DNA methylation and histone modifications relating to gene promoters are catalysts for the development of cancer (33). Much effort has been invested in identifying genetic mutations in cancer. In inherited cancer syndromes this approach has proved successful. Furthermore, mutations early in the genesis of common cancers have also been identified and these are likely to be associated with tumor initiation. In contrast, few specific genetic mutations have been linked to tumor progression, leading Feinberg to suggest that epigenetic changes may be involved. Thus it is possible, for example, that a DNA mutation leads to cellular transformation, but induced changes in the epigenome of the transformed cell enhances the probability that it will be capable of metastasizing. In this scenario, a genetic mutation initiates the cancer but epigenetic change promotes its progression. Epigenetic processes may also be involved in cancer initiation. It is possible that epigenetic change may lead directly to cancer initiation. Alternatively, changes already induced within the epigenome may 'prime' cells in such a way as to promote cellular transformation upon a subsequent DNA mutagenic event. In this case the epigenetic component of the cancer initiation is intricately entwined with the genetic component (13).
Mental Disorders
Cancer
There are two types of mental disorders: neuropsychiatric and idiopathic. Studies suggests that epigenetic mechanisms in gene expression are involved in mental disorders. Gene information in the human genome is "insufficient to specify all the neuronal interconnections in the human brain and hence human brain development requires further information". There has been intense interest in mapping genes underlying mental disorders for the past few decades. Two main approaches which have been used to map genes underlying these disorders are linkage and association studies— neuropsychiatric and idiopathic disorders. (29)
By studying the epigenome, scientists can figure out exactly how and why things happen at the microscopic level. Epigenetic studies facilitated the understanding of many genetic disorders, such as the ones listed below. It offered explanation for certain situations that otherwise did not have answers as to why they occurred.
DNA methylation was the first epigenetic alteration to be observed in cancer cells. "Hypermethylation of CpG islands at tumor suppressor genes switches off these genes, whereas global hypomethylation leads to genome instability and inappropriate activation of oncogenes and transposable elements." There is evidence showing that genomic DNA methylation levels, which are maintained by DNMT enzymes, are delicately balanced within cells. It has been proven that cancer is linked to over-expression of DNMTs in humans. "A number of proteins involved in DNA methylation (e.g. DNMTs and MBDs) directly interact with histone modifying enzymes such as histone methyltransferases (HMTs) and histone deacetylases (HDACs), therefore it is believed that DNA methylation and histone methylation depend on the other." Upsetting this balance will likely have severe consequences on the epigenome and chromatin organization. Numerous factors can influence the DNA methylation levels of a cell without requiring a change in genomic DNA sequence:
- Aging: "With aging in certain tissues there is a general tendency for the genome to become hypomethylated whereas certain CpG islands become hypermethylated, a situation reminiscent of that found in many cancer cells. Whether this age-dependent change in DNA methylation is linked to the increased cancer incidence in later life remains to be determined." (13)
- Diet: "Nutrition supplies the methyl groups for DNA (and histone) methylation via the folate and methionine pathways. Importantly, mammals cannot synthesise folate or methionine and so a diet low in these compounds leads to alterations in DNA methylation." These changes have been proven to be associated with cancer. (13)
- Environment: "Agents such as arsenic and cadmium can have profound effects on DNA methylation. Arsenic causes hypomethylation of the ras gene whereas cadmium induces global hypomethylation by inactivating DNMT1" (13)
DNA Methylation and Cancer
The histone N-terminal tails are essential to maintain chromatin stability and they are subject to numerous modifications. Most modifications have some in transcriptional regulation and so each has the potential to be oncogenic if deregulated deposition leads, for example, to loss of expression of a tumor suppressor gene. (13)
- Acetylation: Histone acetylation tends to open up chromatin structure. Interestingly enough, histone acetyltransferase (HATs) tend to be transcriptional activators whereas histone deacetylases (HDACs) tend to be repressors. (13)
- Methylation: All lysine methyltransferases that target histone N-terminal tails contain a "SET domain". A SET domain possesses lysine methyltransferase activity. Numerous amounts of SET domain-containing proteins are implicated in cancer. For example, is the Suv39 family of enzymes that catalyse methylation of H3K9 is susceptible to cancer. "Transgenic mice devoid of these enzymes are very susceptible to cancer, especially B cell lymphomas." Histone demethylases has recently been identified, but has yet to be linked to cancer. However, such a connection between the two seems probable. (13)
- Phosphorylation: H3S10 and H3S28 are phosphorylated during mitosis. Often, misregulation in this process is associated with a variety of cancers. An example is the Aurora kinases that perform this H3 phosphorylation, which are indeed implicated in cancer. (13)
Histone Modifications and Cancer
Alzheimer's Disease
Alzheimer's disease (AD) is one of the most common neurodegenerative disorders affecting elderly people who are over 65 years of age. Less than 5% of the disease is consistent with the Mendelian form of inheritance. The rest, dubbed as Late Onset Alzheimer's Disease (LOAD), which accounts for over 95% of AD cases, is characterized as a "complex multi-factorial disorder, missing familial traits." Though some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, "they only account for the minority of LOAD cases." Over the past few years emerging data suggests that epigenetic mechanisms and chromatin remodeling on neurodegenerative processes may lead to dementia. Alterations to the epigenomic machinery results in DNA methylation and histone acetylation. Therefore, these changes "trigger alterations on the transcriptional level of genes involved in the pathogenesis of AD, such as APP." (57)
Alzheimer's Association is the world's leading voluntary health organization in Alzheimer's care, support and research. They work on a global, national, and local scale, offering support, care, and treatment to those suffering with Alzheimer's and related dementias. Alzheimer's Association is currently Alzheimer's research's largest, non-profit funder. (58)
Autism
Autism spectrum disorder (ASD) and “autism” are both general terms for a group of complex disorders of brain development. These disorders are characterized, in varying degrees, by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviors. These include autistic disorder, Rett syndrome, childhood disintegrative disorder, pervasive developmental disorder-not otherwise specified (PDD-NOS) and Asperger syndrome. ASD can be associated with intellectual disability, difficulties in motor coordination and attention and physical health issues such as sleep and gastrointestinal disturbances. Some persons with ASD excel in visual skills, music, math and art. Autism appears to have its roots in very early brain development. However, the most obvious signs of autism and symptoms of autism tend to emerge between 2 and 3 years of age (58). In recent years, scientists have identified rare genetic mutations that in and of themselves can produce autism. They have likewise found a large number of genetic changes that increase the risk that a child will develop this disorder. However, fewer than 20 percent of those with an autism spectrum disorder (ASD) harbor identifiable gene defects directly related to the disease (59).
New studies provides strong evidence that, in some cases, the development of autism stems—not from mutations in the genes themselves—but from problems with proteins that help control gene expression inside a cell. Autism scientists have speculated that increased risk of autism might result from problems in the control of gene expression in brain cells. Like DNA mutations, these epigenetic changes can be inherited and run in families. But they can also be caused by exposure to chemicals, lack of crucial nutrients and other many possible stresses. In terms of autism risk, such stresses might have their strongest effect in the womb or in the first months after birth, both crucial periods of brain development. An experiment was conducted where they examined the histone molecules that package and organize the DNA, instead of looking for changes in the actual genes, or DNA molecules, within brain cells. In doing so, they noted marked differences and abnormalities that might account for the disruption of normal gene activity, brain development and brain cell function. Although no single epigenetic change was found in all of the brain tissues affected by autism, the researchers saw an overall pattern of hundreds of abnormal changes scattered throughout this material, which in essence “wraps” a cell’s genes. These changes were most frequently seen on genes associated with increased risk for autism and other neurodevelopmental disorders. “We know that autism is caused by a combination of both genetic and environmental factors," says Autism Speaks Chief Science Officer Geri Dawson, Ph.D. “This study shows that environmental factors may be acting on the genes themselves, disrupting their normal function. This, in turn, helps us better understand how environmental factors may be contributing to autism risk.” (59)
"Autism Speaks was founded
in February 2005 by Bob and
Suzanne Wright,
grandparents of a child
with autism. Their longtime
friend Bernie Marcus
donated $25 million to help
financially launch the
organization. Since then,
Autism Speaks has grown
into the world's leading
autism science and advocacy
organization, dedicated to funding research into the causes, prevention, treatments and a cure for autism; increasing awareness of autism spectrum disorders; and advocating for the needs of individuals with autism and their families. We are proud of what we've been able to accomplish and look forward to continued successes in the years ahead." (43)
Huntington's Disease
Huntington's disease (HD) is a devastating disorder that affects approximately 1 in 10,000 people and is accompanied by neuronal dysfunction and neurodegeneration. HD manifests as a progressive chorea, a decline in mental abilities accompanied by behavioural, emotional and psychiatric problems followed by, dementia, and ultimately, death. The molecular pathology of HD is complex but includes widespread transcriptional dysregulation. Although many transcriptional regulatory molecules have been implicated in the pathogenesis of HD, a growing body of evidence points to the pivotal role of RE1 Silencing Transcription Factor (REST). In HD, REST, translocates from the cytoplasm to the nucleus in neurons resulting in repression of key target genes such as BDNF. Since these original observations, several thousand direct target genes of REST have been identified, including numerous non-coding RNAs including both microRNAs and long non-coding RNAs, several of which are dysregulated in HD. More recently, evidence is emerging that hints at epigenetic abnormalities in HD brain. This in turn, promotes the notion that targeting the epigenetic machinery may be a useful strategy for treatment of some aspects of HD. REST also recruits a host of histone and chromatin modifying activities that can regulate the local epigenetic signature at REST target genes. Collectively, these observations present REST as a hub that coordinates transcriptional, posttranscriptional and epigenetic programmes, many of which are disrupted in HD. We identify several spokes emanating from this REST hub that may represent useful sites to redress REST dysfunction in HD. (60)
The Society is a National, voluntary health organization dedicated to improving the lives of people with Huntington's Disease and their families.
- To promote and support research and medical efforts to eradicate Huntington's Disease.
- To assist people and families affected by Huntington's Disease to cope with the problems presented by the disease.
- To educate the public and health professionals about Huntington's disease. (61)
