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Bianca Keesler

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There are many different things that involve Biology. Some look at the environment
while other aspects look at the many different organisms and their genetic codes. One type of
study is Epigenetics. Epigenetics is the study of genetic variations on the modifications of
chromosomal structures other than their primary sequences. This means that epigenetics is the
study of different genetic variations and how they change without affecting the overall DNA
sequence. Furthermore, two cells with identical DNA can produce different proteins due
epigenetic effects, this commonly happens with identical twins. There is a lot of research that is
being conducted involving twins and how their genes develop. Comparing identical twins and
non-identical twins similarities and differences can be used to estimate the importance of genetic
and environmental influences in a wide range of common conditions such as osteoporosis,
arthritis, diabetes, asthma. One study, conducted by Manel Esteller, a researcher with the Spanish
National Cancer Center in Madrid, Spain, looks at the how the aging of identical twins can lead
them to look and act more alike. For example, one twin may be susceptible to cancer while the
other twin remains healthy. Researchers believe that this may be caused due to changes in the
epigenome. An epigenome is a chemical modification in genes without directly affecting a gene's
DNA but still can result in changes in gene expression. Scientists think that a number of factors,
chemical exposure, dietary habits, and environmental factors, may cause the epigenome changes.
The researchers studied 40 pairs of twins recruited in Spain, Denmark and the United Kingdom;
25 of the pairs were female. The youngest of the pair was 3 and the oldest was 74 years old. All
were asked to complete questionnaires about their health, eating habits, physical activity, history
of medication use and if they consumed tobacco, alcohol, or drugs. The researchers also took
blood samples of each participant so they could analyze and compare similarities and differences
in the epigenome. Results from both the questionnaires and blood samples showed that the

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youngest of the pairs of identical twins had the most identical genomes. However, the oldest pair
of twins ended up having the least identical genetically. A researcher that was part of this study,
also part of the human cancer genetics program at Ohio State, studies methyaltion is both normal
and cancer cells hoping to better understand how the process effects the beginning and
progression of the disease. Due to the fact that identical twins are born with identical sets of
genes, scientists believe that studying the genetic differences will give them insight into how
methyaltion is regulated. Despite them not knowing how changes in DNA methylation occurs,
researchers think that foods, chemical exposures, aging and physical activity levels may
contribute to methylation in cells. The study illustrated that twins who had spent less of their
lives together or had greater differences in their health and medical histories, had the greatest
amounts of methylation. DNA, known as Deoxyribonucleic acid, is the genetic blueprint that
controls how we grow and develop as individuals and as a species. DNA is typically known for
its double helix types shape and helps play a major role in epigenetics. RNA, known as
Ribonucleic acid, can function as a carrier of genetic information, a catalyst of biochemical
reactions, an adapter molecule in protein synthesis, and a structural molecule in cellular
organelles. Throughout this paper there will be terms such as phenotypes, genotypes and alleles
that may be discussed. A phenotype is the outward appearance of an organism while a genotype
is the inheritable information that an organism receives. An allele is an alternative form of a gene
that is located at a specific position on a specific chromosome. These terms will help support the
purpose for writing this paper. Throughout this paper there will be many supporting arguments
based on my view on this topic. The purpose of this paper is to give an explanation of what
epigenetics is and why it is pertinent that the federal government and researchers use funding
towards the reversal of abnormal genes that are thought to cause certain diseases and disorders.

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Bianca Keesler

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Epigenetics hasnt always been around and because of the discovery by certain
researchers; this type of study is fairly new and unexplored. Conrad Hal Waddington was the first
person to create the term epigenetics around the 1940s. Throughout his time researching he
was able to come up with a working definition for the term in 1975. He described epigenetics as
denoting the casual interactions between genes and their products which bring the phenotype
into being. However, in 1997, two scientists, Henikoff and Matzke, were able to narrow down
Waddingtons definition further in an issue of Trends in Genetics. Their definition referred to
modifications in gene expression that are brought about by heritable, but potentially reversible,
changes in chromosomal structure and/or DNA methylation. Another component that
epigenetics deals with is genetic imprinting, which was discovered in the early 1980s. Genetic
imprinting is the laying down of the heritable methylation pattern. This on-off imprinting of a
specific gene expression can be inherited from one generation to the next, this is why children
seem to resemble their parents instead of on just through a chromosomal DNA sequences they
inherit. The inherited pattern of methylation and gene expression depends on the origin of the
DNA; an example would be if an allele is inherited from a mother versus the father, the
expression would be different. Also during development, two copies of a gene dont function
equivalently causing genetic imprinting to occur.
There are three main mechanisms looked at in epigenetics: RNA silencing, DNA
methylation and histone modification, also known as deacetylation. DNA methylation is when an
enzyme attaches a methyl group to a cytosine base in a DNA molecule. A simpler definition
would be a chemical alteration that prevents the reading of protein making instructions contained
in genes. DNA methylation is what plays a role in genetic imprinting. Due to the attachment,
methyl groups can interfere with part of a cells machinery that synthesizes RNA from DNA.
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Interfering with the transcription causes the methylation to stop the production of the protein
encoded in the gene. The good news however, is that DNA methylation is reversible if certain
enzymes removed the methyl groups from cytosine bases. We can also infer that methylation
helps determine the segregation of parts of the genome into active/inactive compartments, these
compartments are crucial to gene expression. Histones are proteins that are soluble in water, that
combine with DNA to form complexes in chromatins and function in regulating gene activity.
Chromatins are twisted, double-stranded, negatively charged DNA spools around positively
charged histone proteins that forms a string like structure. This chromatin structure plays a role
in rendering most of the DNA in a cell off limits to the transcriptional machinery so that only the
necessary segment of DNA is recorded at a given time or place. Modification of the chromatin
related structural proteins provides a dominant means of controlling the transcriptional activity of
individual genes, domains and entire chromosomes. If the structure of the chromatin is dense and
compact, then enzymes are being blocked from accessing a gene for transcription. If the structure
is relaxed and open, then transcription can take place. DNA methylaion and histone modification
also play a role in the onset of diseases with both appearing in disturbed tumors. RNA silencing
refers to nonmutational gene inactivation that can be faithfully cultivated to clones of daughter
cells. Epigenetic silencing can occur by methylation of cytosines and deacetylation of histones,
two processes that appear to act jointly.
Currently the FDA, Food and Drug Administration, is exploring potential new medicines
to help stop epigenetic mutations; one drug being looked at is Vidaza. Vidaza is being used to
help treat Refractory Anemia and Chronic Myelomonocytic Leukemia, both diseases are blood
diseases, the second being a rare blood cancer, that extremely hard to treat. This drug is designed
to treat people with myelodysplastic syndromes, diseases that affect the bone marrow and blood,
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such as the two mentioned above. A person may be prescribed this to help reduce the amount of
blood transfusions they may need or to help improve bone marrow function. This drug, along
with another called Dacogen, is thought to reverse abnormal DNA methylation patterns. Besides
this new drug, there are also new technologies that are being created by B.G.I. (Beijing
Genomics Institute). One type is Chip Sequencing, which is used to identify binding sites of
DNA associated proteins. Another type is MeDiP Sequencing which is being used to analyze
genome-wide DNA methylation based on immunoprecipitation of methylated cytosines. The
final type is called Bisulfate Sequencing and this is used to analyze genome wide DNA
methylation based on bisulfite conversion of methylated cytosines to uracil.
There are numerous reasons for why federal funding should be given to epigenetic
researchers. Atypical DNA methylation has been associated with numerous human diseases, such
as psychiatric diseases that are shown to differently afflict monozygotic (MZ) twins who are
genetically identical. Other developmental diseases including Immunodeficiency, Centomeric
instability, and Facial anomalies (ICF) syndrome, a rare immune disorder, which often results in
defective lymphogenesis and neurodevelopmental disorders Prader-Willi, a hereditary disease
that involves obesity, decreased muscle tone, decreased mental capacity, and trouble producing
little or no hormones, and Angelman Syndrome which is a genetic disorder that causes
developmental delay and neurological problems. Epigenetics is now strongly believed to play
some role in a majority of noninfectious diseases. Evidence is strongly based on different DNA
methylation and histone acetylation patterns in MZ twins and the delayed adult onset of inherited
genetic diseases, such as Amyotrophic Lateral Sclerosis, otherwise known as Lou Gehrig's
disease and Huntingtons chorea. Other diseases, such as Alzheimers, Down syndrome,
Coronary Artery disease, and a developmental syndrome known as Neural Tube defect, have
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been associated with deficiencies in the metabolism of folate menthionime, which provides the
donor methyl group in DNA methylation. Amyotrophic Lateral Sclerosis is a rapidly progressive,
invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for
controlling voluntary muscles. Huntingtons chorea is spastic, involuntary movements of the
body especially of arms, legs and face. Alzheimers disease is a type of dementia that causes
problems with memory, thinking and behavior. Down syndrome is set of mental and physical
symptoms that result from having an extra copy of Chromosome 21, meaning that the person has
forty-seven instead of forty-six. Coronary Artery disease is a narrowing of the small blood
vessels that supply blood and oxygen to the heart. Neural Tube defects are birth defects that
affect the brain and spinal cord. Aberrant DNA methylation patterns are now being investigated
as potential biomarkers and pathway specific therapeutic targets. Unusual histone modifications
have also been associated with diseases such as different types of cancers, as well. Tumors
exhibit overall hypomethylation of normally unmethylated CpG islands. This CpG methylation
within promoters of specific tumor suppressor genes is associated with transcriptional silencing
of those genes and diminished control of cell proliferation. One reason why federal funding
should be given is because of how it can affect stem cell research. Research on the nature
epigenetic modification and means of modifying it so that stomatic cell nuclei could be
reprogrammed to a state equivalent to those embryonic stem cells would make oocytes thus
making embryos unnecessary for generating human embryonic stem cells. Another reason is that
epigenetics has such an effect on different diseases, such as the ones mentioned before. Also
epigenetics has an impact on dietary components as well. Dietary elements can affect DNA
methylation in four different ways. Dietary factors are important in providing and regulating the
supply of methyl groups available for the information of S-adenosylmethionine (universal

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donor). These factors may modify the utilization of methyl groups by processes that include
shifts to DNA methylation activity. A third plausible mechanism relates to DNA methylation
activity and finally, the DNA methylation patterns may influence the response by regulating
genes that influence absorption, metabolism or site of action for the bioactive food components.
An individuals response to dietary interventions will depend in part on their genetic background
(nutrigenetic effects), the cumulative effects of food components on genetic expression profiles
(nutritional transcriptomic and epigenomic effects), the occurrence and activities of proteins
(nutritional proteomic effects) and the dose temporal changes in cellular low molecular weight
compounds (metabolomic effects). Doctors like John Milner, PhD, Chief, Nutritional Science
Research Group, Division of Cancer Prevention, National Cancer Institute, suggest that a
solution may result from three different ways: an increased understanding of genomics, the
associated genetic processes and how they affect the overall phenotype of an individual.
A third reason is that we dont only inherit genes from our parents, we inherit
characteristics, termed epigenetic, that are independent of changes in gene sequences and these
have a major impact on how offspring develop. Inheriting these genes/characteristics is what
sometimes causes offspring to develop diseases or disorders like schizophrenia. The importance
of genetic inheritance has been highlighted in conditions, like schizophrenia, where heritability is
very high but where identical twin concordance is a little better than 50%. In twins discordant for
schizophrenia, the phenotype correlates with DNA methylation levels. Actually having twins in
itself ends up becoming an additional risk factor for developmental disorders. Phenotypic
development of one embryo may influence to co-twin, a concept dubbed mirror-imaging. Take
Autism Spectrum Disorder (ASD) for example, in this case it is possible that developmental
events taking place in one twin can bias evens in the other, such as that one of the two only
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develops ASD. Such influences may further complete the unraveling of genes contributing to the
disorder. Another example is bipolar disorders, a particular gene alleles account less for the
disorder than the source of the allele because the risk depends more on whether the genes are
inherited from the mother or father and less on their identity, a classical type of genetic
inheritance. Another epigenetic contribution to ASD is Rett Syndrome, one of the persistent
developmental disorders that include autism, due to a mutation in the gene encoding the protein
that recognizes and binds to DNA bearing methyl groups, known as MeCP2. There is also a
possibility that imprinting errors make a specific contribution to the development of the ASD
phenotype through the specific genes involved are not known.
A forth reason is that some of the epigenetic patterns are reversible and this can lead to
cures for some of the currently incurable diseases/disorders. Currently, there are three epigenetic
patterns that can be reversed: DNA methylation inhibitors, 5-azacytidine inhibitors and histone
deacylase inhibitors (Trichostatin A). Histone deacetylase is described as a decreased Chronic
Obstructive Lung Disease (COPD) and postulated to play a role in the increased expression of
nuclear factor kB-controlled inflammation. Histone deacetylase inhibitors are being evaluated for
cancer treatment and considered for chemoprevention. Epigenetic silencing of tumor suppressor
genes by methylation of promoter CpG islands is a common mechanism of inactivation in
cancer. Hypermethylation of normally unmethylated CpG islands in the regions of many tumor
suppressor genes, P16, P15, VHL, E-cadherin and hMLHI, correlates well with the loss of
transcription in human cancers. Most of the genes can be reactivated by the addition of 5-aza-2deoxycytidine (5-aza) a demethylating agent. Trichostatin A, a histone acetylator, rarely
reactivates genes alone however, in general, it appears that most inactivated genes need
pretreatment with 5-aza to achieve substantial reexpression. The potential reversibility of these
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epigenetic changes in tumor cells is what attracts pharmacologic with demethylating and
deacetylating agents. Knowledge taken from methylated tumor suppressor gene studies may be
useful in the diagnosis, early detection, and treatment of lung cancer and precursor lesions. In
one study, the methylation of the P16 tumor suppressor gene was looked at because of its
association with the loss of expression in precursor lesions of lung cancer. The P16 gene was
coordinately methylated in 75% of the carcinoma insitu lesions adjacent to the squamous cell
carcinomas where this change was located. The frequency of P16 methylation increased as the
disease progressed form basal cell hyperplasia, about 17%, to squamous metaplasia, about 24%,
to carcinoma in situ, about 50%. Methylation of the gene was then associated with the loss of
expression in both tumors and precursor lesions. This revealed that both of the alleles were
inactivated. This data was then used to link aberrant methylation of the P16 gene to the early
stages of lung cancer thus suggesting a potential use of using this epigenetic change as a
biomarker for the early detection of patients with lung cancer or at risk of developing the disease.
Increased promoter methylation of multiple genes in DNA, isolated from sputum, has been used
as a risk biomarker for lung cancer.
Finally, if there was federal funding for epigenetic research, researchers, companies and
organizations could have the funding they need to find cures for certain diseases/disorders. One
research institute, the Nutritional Science Research Group (NSRG), is located within the
Division of Cancer Prevention at the National Cancer Institute (NCI) which is a part of the
National Institutes of Health (NIH). This group focuses on diet and nutrition as it pertains to
cancer prevention. Some of NSRGs main goals deal with diet, epigenetic events, and cancer
prevention, nutritional modulation of genetic pathways, and the identification and
characterization of molecular targets for nutrients in various cancer sites. Another facility is the
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Beijing Genomics Institute (B.G.I.). This facility believes that genome DNA methylation is a
major epigenetic system that modifies gene expression, regulation, cell differentiation, diverse
biological processes and so on. A team of Chinese researchers decoded the essentially complete
methylome (an inventory of all the bases that are methylated) of the human genome using
peripheral blood mononuclear cells (PBMCs). The research was part of the YsnHuang (YH)
project and aims to sequence 100 Chinese individuals in 3 years to accelerate the discovery of
disease genes and mutations in an Asian population. The methylome was generated from the
same donor whose genome was deciphered in the YH project. The methylome was examined at
20 distinct features including regulatory, protein-coding, non-coding and repeat sequences. The
integration of the data with the previously determined genome sequence of the same Asian
individual, allowed the identification of allele-specific methylation (ASM) differences between
the methylomes of the genomes inherited from either parent. This revealed that ASM was highly
correlated with allele-specific gene expression (ASE) which indicated that parental gene
imprinting (that is the favored expression of the genes inherited from one parent) may be more
common than previously thought. Another organization is the Human Epigenome Project. This
organization aims to identify, catalogue and interpret genome-wide DNA methylation patterns of
all human genes in all major tissues. Methylation is the only flexible genomic parameter that can
change genome function under outside influences. Methylation in turn constitutes the main and
so far missing link between genetics, disease and the environment that is widely thought to play
a decisive role in the aetiology of virtually all human pathologies. Methylation occurs naturally
on cytosine bases at CpG sequences and is involved in controlling the correct expression of
genes. Different methylated cytosines turn into distinct patterns that are specific for tissue type
and disease state. Such methylation variable positions (MVPs) are common epigenetic markers

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and like single nucleotide polymorphisms (SNPs), they promise to significantly advance our
ability to understand and diagnose human disease. Another aim was to generate tissue-specific
DNA methylation reference profiles of the human genome. They approached this by treating the
genomic DNA with sodium bisulphite which converts unmethylated cytosines into uracil but
doesnt affect methylated cytosines. After following PCR amplification and sequencing of
selected amplicons from bisulphite-converted DNA, the degree of methylation was determined
by comparison of the corresponding signal ratios at CpG dinucleotides, the predominant sites of
DNA methylation. Some of the facilities working together in this project are The Welcome Trust
Sanger Institute, Epigenomics AG, BGI and the Centre National de Genotypage. The Center for
Cancer Epigenetics (CCE) is another facility that focuses on the study of heritable and acquired
changes that affect gene expression and cellular differentiation without DNA sequence alteration.
It is co-directed by Sharon Dent, Ph.D., and Jean-Pierre Issa, M.D and its main goal is to define
the full spectrum of epigenetic changes that occur in cancers, to discover the molecular causes of
these changes, and to translate that newly gained knowledge into the clinic in the form of novel,
epigenetic based therapies.
If there was to be more federal funding being used for epigenetics then we could possibly
find cures for diseases, such a cancer, which are killing many people each day and diagnosing
millions more. There are many reasons for having more federal funding and some of these
reasons are that some epigenetic changes can be reversed, there are many different diseases that
may have cures if more funding is put forth and that there have been programs/companies that
are focusing on finding these cures. Every day brings about new hope for cures for diseases and
because science is constantly evolving and getting better, if epigenetics is looked at for more
options, then the next day we could have a cure for a debilitating disease.
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