Epigenetics Are Different Than Mutations in That Mutations

The behavior of a person’south genes doesn’t only depend on the genes’ Deoxyribonucleic acid sequence – it’due south also affected past and so-chosen epigenetic factors. Changes in these factors can play a critical role in disease.

The external
environment‘s effects upon
can influence
disease, and some of these effects tin can be inherited in humans. Studies investigating how ecology factors impact the genetics of an individual’southward
are difficult to pattern. Notwithstanding, in certain parts of the earth in which social systems are highly centralized, environmental information that might have influenced families can be obtained. For example, Swedish scientists recently conducted investigations examining whether diet affected the expiry rate associated with cardiovascular affliction and diabetes and whether these effects were passed from parents to their children and grandchildren (Kaati
et al., 2002). These researchers estimated how much access individuals had to nutrient past examining records of annual harvests and food prices in Sweden across 3 generations of families, starting as far back as the 1890s. These researchers found that if a begetter did not take enough nutrient available to him during a
critical catamenia
in his
only before puberty, his sons were less likely to die from cardiovascular disease. Remarkably, death related to diabetes increased for children if food was plentiful during this critical period for the
grandpa, but it decreased when backlog food was available to the father. These findings suggest that diet tin can cause changes to genes that are passed down though generations by the males in a family, and that these alterations can impact susceptibility to sure diseases. But what are these changes, and how are they remembered? The answers to questions such equally these prevarication in the concept of epigenetics.

What Is Epigenetics? How Do Epigenetic Changes Affect Genes?

Epigenetics involves genetic control by factors other than an individual’s
sequence. Epigenetic changes tin switch genes on or off and determine which proteins are transcribed.

Epigenetics is involved in many normal cellular processes. Consider the fact that our cells all take the same Dna, but our bodies contain many different types of cells: neurons, liver cells, pancreatic cells, inflammatory cells, and others. How tin this be? In short, cells, tissues, and organs differ because they have sure sets of genes that are “turned on” or expressed, likewise every bit other sets that are “turned off” or inhibited. Epigenetic
is one style to turn genes off, and it can contribute to differential expression. Silencing might also explicate, in office, why genetic twins are not phenotypically identical. In improver, epigenetics is important for X-chromosome inactivation in female person mammals, which is necessary and then that females do not take twice the number of X-chromosome gene products as males (Egger
et al., 2004). Thus, the significance of turning genes off via epigenetic changes is readily apparent.

Within cells, there are three systems that tin can interact with each other to silence genes: Deoxyribonucleic acid
modifications, and RNA-associated silencing (Effigy 1; Egger
et al., 2004).

Deoxyribonucleic acid Methylation

DNA methylation
is a chemic process that adds a methyl group to DNA. It is highly specific and e’er happens in a region in which a
is located next to a
nucleotide that is linked past a phosphate; this is called a CpG site (Egger
et al., 2004; Jones & Baylin, 2002; Robertson, 2002). CpG sites are methylated by one of three enzymes called Deoxyribonucleic acid methyltransferases (DNMTs) (Egger
et al., 2004; Robertson, 2002). Inserting methyl groups changes the appearance and structure of DNA, modifying a
gene‘s interactions with the machinery within a
jail cell‘south
that is needed for
transcription. DNA methylation is used in some genes to differentiate which gene copy is inherited from the father and which cistron copy is inherited from the mother, a phenomenon known as

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Histone Modifications

are proteins that are the principal components of
chromatin, which is the complex of Deoxyribonucleic acid and proteins that makes up chromosomes. Histones act as a spool effectually which Deoxyribonucleic acid can wind. When histones are modified subsequently they are translated into poly peptide (i.due east., post-translation modification), they can influence how chromatin is arranged, which, in plow, can determine whether the associated chromosomal DNA will be transcribed. If chromatin is non in a compact form, information technology is active, and the associated Deoxyribonucleic acid tin exist transcribed. Conversely, if chromatin is condensed (creating a complex called
heterochromatin), then it is inactive, and DNA transcription does not occur.

There are two main means histones tin can be modified:
and methylation. These are chemical processes that add either an acetyl or methyl grouping, respectively, to the amino acid lysine that is located in the histone. Acetylation is normally associated with active chromatin, while deacetylation is mostly associated with heterochromatin. On the other hand, histone methylation can be a
for both active and inactive regions of chromatin. For instance, methylation of a particular lysine (K9) on a specific histone (H3) that marks silent DNA is widely distributed throughout heterochromatin. This is the type of epigenetic change that is responsible for the inactivated
X chromosome
of females. In contrast, methylation of a different lysine (K4) on the aforementioned histone (H3) is a marker for active genes (Egger
et al., 2004).

RNA-Associated Silencing

Genes can too be turned off by
when it is in the class of antisense transcripts, noncoding RNAs, or RNA
interference. RNA might touch on
gene expression
past causing heterochromatin to form, or by triggering histone modifications and Deoxyribonucleic acid methylation (Egger
et al., 2004).

Epigenetics and Disease: Some Examples

This three-column table lists several diseases caused by epigenetic changes along with their symptoms and etiologies.

While epigenetic changes are required for normal development and health, they can also be responsible for some disease states. Disrupting any of the three systems that contribute to epigenetic alterations tin crusade aberrant activation or silencing of genes. Such disruptions accept been associated with
cancer, syndromes involving chromosomal instabilities, and mental retardation (Table i).

Epigenetics and Cancer

The first man disease to be linked to epigenetics was cancer, in 1983. Researchers establish that diseased tissue from patients with colorectal cancer had less Dna methylation than normal tissue from the same patients (Feinberg & Vogelstein, 1983). Because methylated genes are typically turned off, loss of DNA methylation tin can cause abnormally loftier gene activation by altering the organisation of chromatin. On the other hand, likewise much methylation can disengage the piece of work of protective
tumor suppressor

As previously mentioned, Dna methylation occurs at CpG sites, and a majority of CpG cytosines are methylated in mammals. All the same, there are stretches of Deoxyribonucleic acid almost
regions that have higher concentrations of CpG sites (known equally CpG islands) that are free of methylation in normal cells. These CpG islands go excessively methylated in cancer cells, thereby causing genes that should non be silenced to plough off. This abnormality is the trademark epigenetic alter that occurs in tumors and happens early in the evolution of cancer (Egger
et al., 2004; Robertson, 2002; Jones & Baylin, 2002). Hypermethylation of CpG islands can cause tumors by shutting off tumor-suppressor genes. In fact, these types of changes may be more than common in human cancer than DNA sequence mutations (Effigy two).

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Furthermore, although epigenetic changes exercise not modify the sequence of DNA, they can cause mutations. About half of the genes that crusade familial or inherited forms of cancer are turned off past methylation. Well-nigh of these genes usually suppress tumor formation and assist repair DNA, including O6-methylguanine-Dna methyltransferase (MGMT), MLH1
cyclin-dependent kinase
inhibitor 2B (CDKN2B), and
RASSF1A. For example, hypermethylation of the promoter of
causes the number of G-to-A mutations to increase (Figure 2).

Hypermethylation can too lead to instability of microsatellites, which are repeated sequences of DNA. Microsatellites are common in normal individuals, and they ordinarily consist of repeats of the dinucleotide CA. Besides much methylation of the promoter of the
DNA repair
can make a
unstable and lengthen or shorten it (Figure 2). Microsatellite instability has been linked to many cancers, including colorectal, endometrial, ovarian, and gastric cancers (Jones & Baylin, 2002).

This diagram illustrates deoxynucleoside analogues such as 5-aza-2-deoxycytidine being incorporated into DNA strands during the process of DNA replication. Once the analogues are incorporated into the newly synthesized DNA in place of cytosine, DNA methyltransferases covalently bind to the analogues, resulting in less active enzyme. As a consequence of this depletion, the newly synthesized strands of DNA are demethylated.

Figure 2: Machinery of action of nucleoside analogue inhibitors.

Deoxynucleoside analogues such equally 5-aza-2-deoxycytidine (depicted by Z) are converted into the triphosphate within S-phase cells and are incorporated in place of cytosine into Dna. Ribonucleosides such as 5-azacytidine or zebularine are reduced at the diphosphate level by ribonucleotide reductase for incorporation (non shown). Once in DNA, the fraudulent bases form covalent bonds with Deoxyribonucleic acid methyltransferases (DNMTs), resulting in the depletion of active enzymes and the demethylation of Deoxyribonucleic acid. Pink circles, methylated CpG; cream circles, unmethylated CpG.

© 2004 Nature Publishing Grouping Egger, Chiliad.
et al.
Epigenetics in man disease and prospects for epigenetic therapy.
460 (2004). All rights reserved.

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Epigenetics and Mental Retardation

This micrograph shows 46 black, X-shaped, metaphase chromosomes against a white background. An arrow points to the end of the long arm of the X chromosome where there is a constricted site. Due to the constricted site, the end of the chromosome appears detached, giving the X chromosome a fragile appearance.

Fragile X
is the most frequently inherited mental inability, especially in males. Both sexes can be affected by this condition, but considering males merely have one Ten
chromosome, i fragile Ten will bear upon them more than severely. Indeed, fragile 10 syndrome occurs in approximately one in 4,000 males and 1 in 8,000 females. People with this syndrome have severe intellectual disabilities, delayed verbal development, and “autistic-like” beliefs (Penagarikano
et al., 2007).

Fragile X syndrome gets its name from the way the role of the X chromosome that contains the gene aberration looks under a microscope; information technology ordinarily appears equally if it is hanging by a thread and easily brittle (Figure 3). The syndrome is caused by an aberration in the
(fragile X mental retardation 1) gene. People who do not have frail 10 syndrome have vi to 50 repeats of the trinucleotide CGG in their
gene. Still, individuals with over 200 repeats take a total
mutation, and they unremarkably show symptoms of the syndrome. Besides many CGGs cause the CpG islands at the promoter region of the
gene to go methylated; normally, they are not. This methylation turns the gene off, stopping the
cistron from producing an important
chosen frail Ten mental retardation poly peptide. Loss of this specific protein causes fragile X syndrome. Although a lot of attention has been given to the CGG expansion mutation as the cause of fragile 10, the epigenetic change associated with
methylation is the real syndrome culprit.

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Fragile 10 syndrome is not the only disorder associated with mental retardation that involves epigenetic changes. Other such conditions include Rubenstein-Taybi, Coffin-Lowry, Prader-Willi, Angelman, Beckwith-Wiedemann, ATR-X, and Rett syndromes (Table i).

Combating Diseases with Epigenetic Therapy

Considering so many diseases, such as cancer, involve epigenetic changes, it seems reasonable to try to counteract these modifications with epigenetic treatments. These changes seem an ideal target because they are by nature reversible, unlike DNA sequence mutations. The most popular of these treatments aim to alter either DNA methylation or histone acetylation.

Inhibitors of DNA methylation can reactivate genes that accept been silenced. Two examples of these types of drugs are
and 5-aza-2′-deoxycytidine (Egger
et al., 2004). These medications work by acting similar the nucleotide cytosine and incorporating themselves into Deoxyribonucleic acid while information technology is replicating. Afterwards they are incorporated into DNA, the drugs block DNMT enzymes from acting, which inhibits Deoxyribonucleic acid methylation.

Drugs aimed at histone modifications are called
histone deacetylase
(HDAC) inhibitors. HDACs are enzymes that remove the acetyl groups from DNA, which condenses chromatin and stops transcription. Blocking this process with HDAC inhibitors turns on factor expression. The most mutual HDAC inhibitors include phenylbutyric acid, SAHA, depsipeptide, and valproic acid (Egger
et al., 2004).

Caution in using epigenetic therapy is necessary because epigenetic processes and changes are so widespread. To exist successful, epigenetic treatments must be selective to irregular cells; otherwise, activating gene transcription in normal cells could make them cancerous, so the treatments could crusade the very disorders they are trying to counteract. Despite this possible drawback, researchers are finding ways to specifically target aberrant cells with minimal damage to normal cells, and epigenetic therapy is beginning to wait increasingly promising.

References and Recommended Reading

Egger, G.,
et al. Epigenetics in human illness and prospects for epigenetic therapy.
429, 457–463 (2004) doi:10.1038/nature02625 (link to article)

Feinberg, A.P., & Vogelstein, B. Hypomethylation distinguishes genes of some human being cancers from their normal counterparts.
301, 89–92 (1983) doi:10.1038/301089a0 (link to article)

Jones, P. A., & Baylin, S. B. The fundamental role of epigenetic events in cancer.
Nature Reviews Genetics
iii, 415–428 (2002) doi:10.1038/nrg816 (link to commodity)

Kaati, G.,
et al. Cardiovascular and diabetes mortality determined by nutrition during parents’ and grandparents’ tedious growth period.
European Journal of Human being Genetics
ten, 682–688 (2002)

Penagarikano, O.,
et al. The pathophysiology of fragile X syndrome.
Annual Review of Genomics and Human Genetics
viii, 109–129 (2007) doi:ten.1146/annurev.genom.8.080706.092249

Robertson, Thousand. D. DNA methylation and chromatin: Unraveling the tangled web.
21, 5361–5379 (2002) doi:10.1038/sj.onc.1205609

Epigenetics Are Different Than Mutations in That Mutations

Source: http://www.nature.com/scitable/topicpage/epigenetic-influences-and-disease-895

Originally posted 2022-08-04 16:46:12.

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