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Epigenetic effects in humans
1. Genomic imprinting and related disorders
Some human disorders are associated with genomic
imprinting, a phenomenon in mammals where the father and mother
contribute different epigenetic patterns for specific genomic loci
in their germ cells. The best-known case of imprinting in human
disorders is that of Angelman syndrome and Prader-Willi
syndrome—both can be produced by the same genetic mutation,
chromosome 15q partial deletion, and the particular syndrome that
will develop depends on whether the mutation is inherited from the
child's mother or from their father. This is due to the presence of
genomic imprinting in the region. Beckwith-Wiedemann syndrome is
also associated with genomic imprinting, often caused by
abnormalities in maternal genomic imprinting of a region on
chromosome 11.
2. Transgenerational epigenetic observations
Marcus Pembrey and colleagues also observed in the Överkalix study
that the paternal (but not maternal) grandsons Please clarify of
Swedish boys who were exposed during preadolescence to famine in the
19th century were less likely to die of cardiovascular disease; if
food was plentiful then diabetes mortality in the grandchildren
increased, suggesting that this was a transgenerational epigenetic
inheritance. The opposite effect was observed for females—the
paternal (but not maternal) granddaughters of women who experienced
famine while in the womb (and therefore while their eggs were being
formed) lived shorter lives on average.
3. Cancer and developmental abnormalities
A variety of compounds are considered as
epigenetic carcinogens—they result in an increased incidence of
tumors, but they do not show mutagen activity (toxic compounds or
pathogens that cause tumors incident to increased regeneration
should also be excluded). Examples include diethylstilbestrol,
arsenite, hexachlorobenzene, and nickel compounds.
Many teratogens exert specific effects on the fetus by epigenetic
mechanisms. While epigenetic effects may preserve the effect of a
teratogen such as diethylstilbestrol throughout the life of an
affected child, the possibility of birth defects resulting from
exposure of fathers or in second and succeeding generations of
offspring has generally been rejected on theoretical grounds and for
lack of evidence. However, a range of male-mediated abnormalities
have been demonstrated, and more are likely to exist. FDA label
information for Vidaza(tm), a formulation of 5-azacitidine (an
unmethylatable analog of cytidine that causes hypomethylation when
incorporated into DNA) states that "men should be advised not to
father a child" while using the drug, citing evidence in treated
male mice of reduced fertility, increased embryo loss, and abnormal
embryo development. In rats, endocrine differences were observed in
offspring of males exposed to morphine. In mice, second generation
effects of diethylstilbesterol have been described occurring by
epigenetic mechanisms.
Recent studies have shown that the Mixed Lineage Leukemia (MLL) gene
causes leukemia by rearranging and fusing with other genes in
different chromosomes, which is a process under epigenetic control.
Other investigations have concluded that alterations in histone
acetylation and DNA methylation occur in various genes influencing
prostate cancer.
In 2008, the National Institutes of Health announced that $190
million had been earmarked for epigenetics research over the next
five years. In announcing the funding, government officials noted
that epigenetics has the potential to explain mechanisms of aging,
human development, and the origins of cancer, heart disease, mental
illness, as well as several other conditions. Some investigators,
like Randy Jirtle, PhD, of Duke University Medical Center, think
epigenetics may ultimately turn out to have a greater role in
disease than genetics.
4. DNA methylation in cancer
DNA methylation is an important regulator of gene
transcription and a large body of evidence has demonstrated that
aberrant DNA methylation is associated with unscheduled gene
silencing, and the genes with high levels of 5-methylcytosine in
their promoter region are transcriptionally silent. DNA methylation
is essential during embryonic development, and in somatic cells,
patterns of DNA methylation are generally transmitted to daughter
cells with a high fidelity. Aberrant DNA methylation patterns have
been associated with a large number of human malignancies and found
in two distinct forms: hypermethylation and hypomethylation compared
to normal tissue. Hypermethylation is one of the major epigenetic
modifications that repress transcription via promoter region of
tumour suppressor genes. Hypermethylation typically occurs at CpG
islands in the promoter region and is associated with gene
inactivation. Global hypomethylation has also been implicated in the
development and progression of cancer through different mechanisms.
[edit] Variant histones H2A in cancerThe histone variants of the H2A
family are highly conserved in mammals, playing critical roles in
regulating many nuclear processes by altering chromatin structure.
One of the key H2A variants, H2A.X, marks DNA damage, facilitating
the recruitment of DNA repair proteins to restore genomic integrity.
Another variant, H2A.Z, plays an important role in both gene
activation and repression. A high level of H2A.Z expression is
ubiquitously detected in many cancers and is significantly
associated with cellular proliferation and genomic instability.
5. Cancer Treatment
Current research has shown that epigenetic
pharmaceuticals could be a putative replacement or adjuvant therapy
for currently accepted treatment methods such as radiation and
chemotherapy, or could enhance the effects of these current
treatments. It has been shown that the epigenetic control of the
proto-onco regions and the tumor suppressor sequences by
conformational changes in histones directly affects the formation
and progression of cancer. Epigenetics also has the factor of
reversibility, a characteristic that other cancer treatments do not
offer.
Drug development has mainly focused on Histone Acetyltransferase
(HAT) and Histone Deactylase (HDAC), including the introduction of
the new pharmaceutical Vorinostat, a HDAC inhibitor, to the market.
HDAC specifically has been shown to play an integral role in the
progression of oral squamous cancer
Current front-runner candidates for new drug targets are Histone
Lysine Methyltransferases (KMT) and Protein Arginine
Methyltransferases (PRMT).
[edit] Twin studiesRecent studies involving both dizygotic and
monozygotic twins have produced some evidence of epigenetic
influence in humans.
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