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Epigenetics: The Science of Change



For nearly a century after the term “epigenetics” first surfaced on the printed page, researchers, physicians, and others poked around in the dark crevices of the gene, trying to untangle the clues that suggested gene function could be altered by more than just changes in sequence. Today, a wide variety of illnesses, behaviors, and other health indicators already have some level of evidence linking them with epigenetic mechanisms, including cancers of almost all types, cognitive dysfunction, and respiratory, cardiovascular, reproductive, autoimmune, and neurobehavioral illnesses. Known or suspected drivers behind epigenetic processes include many agents, including heavy metals, pesticides, diesel exhaust, tobacco smoke, polycyclic aromatic hydrocarbons, hormones, radioactivity, viruses, bacteria, and basic nutrients. In the past five years, and especially in the past year or two, several groundbreaking studies have focused fresh attention on epigenetics. Interest has been enhanced as it has become clear that understanding epigenetics and epigenomics—the genomewide distribution of epigenetic changes—will be essential in work related to many other topics requiring a thorough understanding of all aspects of genetics, such as stem cells, cloning, aging, synthetic biology, species conservation, evolution, and agriculture.
Matt Ray/EHP
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Environmental Health Perspectives
or nearly a century after the term “epigenetics
first surfaced on the printed page, researchers,
physicians, and others poked around in the dark
crevices of the gene, trying to untangle the clues
that suggested gene function could be altered by
more than just changes in sequence. Today, a wide
variety of illnesses, behaviors, and other health
indicators already have some level of evidence
linking them with epigenetic mechanisms, includ-
ing cancers of almost all types, cognitive dysfunc-
tion, and respiratory, cardiovascular, reproductive,
autoimmune, and neurobehavioral illnesses. Known
or suspected drivers behind epigenetic processes
include many agents, including heavy metals,
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VOLUME 114 | NUMBER 3 | March 2006
A 161
pesticides, diesel exhaust, tobacco smoke, poly-
cyclic aromatic hydrocarbons, hormones, radioac-
tivity, viruses, bacteria, and basic nutrients.
In the past five years, and especially in the
past year or two, several groundbreaking studies
have focused fresh attention on epigenetics.
Interest has been enhanced as it has become clear
that understanding epigenetics and epigenomics—
the genomewide distribution of epigenetic
changes—will be essential in work related to many
other topics requiring a thorough understanding
of all aspects of genetics, such as stem cells,
cloning, aging, synthetic biology, species conser-
vation, evolution, and agriculture.
Epigenetics: The Science of Change
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RNA pol II
RNA pol II
Methylated CpG pair
Acetylated histone tail
Deacetylated histone tail
Methyltranferases attach
methyl groups to DNA
One Epigenetic Mechanism for Repressing Transcription
Methyl groups (CH
attach to cytosine bases
Repression of transcription—the transfer of
genetic information from DNA to RNA—is
one route by which epigenetic mechanisms
can adversely impact health.
Protein complexes, recruited to
methylated DNA, remove acetyl
groups and repress transcription
Multiple Mechanisms
The word “epigenetic” literally means “in
addition to changes in genetic sequence.”
The term has evolved to include any
process that alters gene activity without
changing the DNA sequence, and leads to
modifications that can be transmitted to
daughter cells (although experiments show
that some epigenetic changes can be
reversed). There likely will continue to be
debate over exactly what the term means
and what it covers.
Many types of epigenetic processes have
been identified—they include methylation,
acetylation, phosphorylation, ubiquityla-
tion, and sumolyation. Other epigenetic
mechanisms and considerations are likely
to surface as work proceeds. Epigenetic
processes are natural and essential to many
organism functions, but if they occur
improperly, there can be major adverse
health and behavioral effects.
Perhaps the best known epigenetic
process, in part because it has been easiest to
study with existing technology, is DNA
methylation. This is the addition or removal
of a methyl group (CH
), predominantly
where cytosine bases occur consecutively.
DNA methylation was first confirmed to
occur in human cancer in 1983, and has
since been observed in many other illnesses
and health conditions.
Another significant epigenetic process
is chromatin modification. Chromatin is
the complex of proteins (histones) and
DNA that is tightly bundled to fit into the
nucleus. The complex can be modified by
substances such as acetyl groups (the
process called acetylation), enzymes, and
some forms of RNA such as microRNAs
and small interfering RNAs. This modifica-
tion alters chromatin structure to influence
gene expression. In general, tightly folded
chromatin tends to be shut down, or not
expressed, while more open chromatin is
functional, or expressed.
One effect of such processes is imprint-
ing. In genetics, imprinting describes the
condition where one of the two alleles of a
typical gene pair is silenced by an epigenet-
ic process such as methylation or acetyla-
tion. This becomes a problem if the
expressed allele is damaged or contains a
variant that increases the organisms vulner-
ability to microbes, toxic agents, or other
harmful substances. Imprinting was first
identified in 1910 in corn, and first con-
firmed in mammals in 1991.
Researchers have identified about 80
human genes that can be imprinted,
although that number is subject to debate
since the strength of the evidence varies.
That approximate number isnt likely to
rise much in years to come, writes a team
including Ian Morison, a senior research
fellow in the Cancer Genetics Laboratory
at New Zealand’s University of Otago, in
the August 2005
Trends in Genetics
. Others
in the field disagree. Randy Jirtle, a profes-
sor of radiation oncology at Duke Univ-
ersity Medical Center, and his colleagues
estimated in the June 2005 issue of
Genome Research
that there could be about
600 imprinted genes in mice; in an
October 2005 interview Jirtle said hes
anticipating a similar tally for humans,
even though the known imprintable genes
of mice and people have an overlap of only
about 35%.
Links to Disease
Among all the epigenetics research con-
ducted so far, the most extensively studied
disease is cancer, and the evidence linking
epigenetic processes with cancer is becom-
ing “extremely compelling,” says Peter
Jones, director of the University of South-
ern Californias Norris Comprehensive
Cancer Center. Halfway around the
world, Toshikazu Ushijima is of the same
mind. The chief of the Carcinogenesis
Division of Japans National Cancer
Center Research Institute says epigenetic
mechanisms are one of the five most
important considerations in the cancer
field, and they account for one-third to
one-half of known genetic alterations.
Many other health issues have drawn
attention. Epigenetic immune system
effects occur, and can be reversed, according to
research published in the November–
December 2005 issue of the
Journal of
Proteome Research
by Nilamadhab Mishra,
an assistant professor of rheumatology at
the Wake Forest University School of Med-
icine, and his colleagues. The team says it’s
the first to establish a specific link between
aberrant histone modification and mecha-
nisms underlying lupus-like symptoms in
mice, and they confirmed that a drug in
the research stage, trichostatin A, could
reverse the modifications. The drug
appears to reset the aberrant histone modi-
fication by correcting hypoacetylation at
two histone sites.
Lupus has also been a focus of Bruce
Richardson, chief of the Rheumatology
Section at the Ann Arbor Veterans Affairs
Medical Center and a professor at the
University of Michigan Medical School. In
studies published in the May–August 2004
issue of
International Reviews of Im-
and the October 2003 issue
Clinical Immunology
, he noted that
pharmaceuticals such as the heart drug pro-
cainamide and the antihypertensive agent
hydralazine cause lupus in some people,
and demonstrated that lupus-like disease in
mice exposed to these drugs is linked with
DNA methylation alterations and interrup-
tion of signaling pathways similar to those
in people.
Substantial Changes
Most epigenetic modification, by whatev-
er mechanism, is believed to be erased
with each new generation, during gameto-
genesis and after fertilization. However,
one of the more startling reports published
in 2005 challenges this belief and suggests
that epigenetic changes may endure in at
least four subsequent generations of
Michael Skinner, a professor of molecu-
lar biosciences and director of the Center
for Reproductive Biology at Washington
State University, and his team described in
the 3 June 2005 issue of
how they
briefly exposed pregnant rats to individual
relatively high levels of the insecticide
methoxychlor and the fungicide vinclo-
zolin, and documented effects such as
decreased sperm production and increased
male infertility in the male pups. Digging
for more information, they found altered
DNA methylation of two genes. As they
continued the experiment, they discovered
the adverse effects lasted in about 90% of
the males in all four subsequent genera-
tions they followed, with no additional pes-
ticide exposures.
The findings are not known to have
been reproduced. If they are reproducible,
however, it could “provide a new paradigm
for disease etiology and basic mechanisms
in toxicology and evolution not previously
appreciated,” says Skinner. He and his col-
leagues are conducting follow-up studies,
assessing many other genes and looking at
other effects such as breast and skin
tumors, kidney degeneration, and blood
Other studies have found that epigenet-
ic effects occur not just in the womb, but
over the full course of a human life span.
Manel Esteller, director of the Cancer
Epigenetics Laboratory at the Spanish
National Cancer Center in Madrid, and his
colleagues evaluated 40 pairs of identical
twins, ranging in age from 3 to 74, and
found a striking trend, described in the
26 July 2005 issue of
Proceedings of the
National Academy of Sciences
. Younger twin
pairs and those who shared similar lifestyles
and spent more years together had very
similar DNA methylation and histone
acetylation patterns. But older twins, espe-
cially those who had different lifestyles
and had spent fewer years of their lives
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Epigenetics: The Science of Change
together, had much different patterns in
many different tissues, such as lymphocytes,
epithelial mouth cells, intra-abdominal fat,
and selected muscles.
As one example, the researchers found
four times as many differentially expressed
genes between a pair of 50-year-old twins
compared to 3-year-old twins, and the 50-
year-old twin with more DNA hypo-
methylation and histone hyperacetylation
(the epigenetic changes usually associated
with transcriptional activity) had the high-
er number of overexpressed genes. The
degree of epigenetic change therefore was
directly linked with the degree of change
in genetic function.
Sometimes the effects of epigenetic
mechanisms show up in living color.
Changes in the pigmentation of mouse
pup fur, ranging from yellow to brown,
were directly tied to supplementation of
the pregnant mothers diet with vitamin
, folic acid, choline, and betaine,
according to studies by Jirtle and Robert
Waterland published in August 2003 (issue
15) in
Molecular and Cellular Biology
. The
color changes were directly linked to alter-
ations in DNA methylation. In a study
forthcoming in the April 2006 issue of
, Jirtle and his colleagues also induced
these alterations through maternal inges-
tion of genistein, the major phytoestrogen
in soy, at doses comparable to those a
human might receive from a high-soy diet.
The methylation changes furthermore
appeared to protect the mouse offspring
against obesity in adulthood, although
there are hints that genistein may also
cause health problems, via additive or syn-
ergistic effects on DNA methylation, when
it interacts with other substances such as
folic acid.
Other Drivers of Change
Substances arent the only sources of epi-
genetic changes. The licking, grooming,
and nursing methods that mother rats use
with their pups can affect the long-term
behavior of their offspring, and those
results can be tied to changes in DNA
methylation and histone acetylation at a
glucocorticoid receptor gene promoter in
the pups hippocampus. This finding was
published in the August 2004 issue of
Nature Neuroscience by Moshe Szyf, a pro-
fessor in McGill Universitys Department
of Pharmacology and Therapeutics, and
his colleagues. In the same study, the
researchers found that the effects werent
written in stone; giving the drug tricho-
statin A to older pups could help reverse
the effects of poor maternal care received
when they were younger. In the 6 June
2003 Journal of Biological Chemistry and
the 23 November 2005 Journal of
Neuroscience, Szyf and many of the same
colleagues also demonstrated that giving
the amino acid
L-methionine to older
pups could negate the benefits of high-
quality maternal care received when they
were younger.
Along with behavior, mental health
may be affected by epigenetic changes, says
Arturas Petronis, head of the Krembil
Family Epigenetics Laboratory at the
Centre for Addiction and Mental Health in
Toronto. His lab is among the first in the
world, and still one of only a few, to study
links between epigenetics and psychiatry.
He and his colleagues are conducting large-
scale studies investigating links between
schizophrenia and aberrant methylation,
and he says understanding epigenetic
mechanisms is one of the highest priorities
in human disease biology research. “We
really need some radical revision of key
principles of the traditional genetic
research program,” he says. “Epigenetics
brings a new perspective on the old prob-
lem and new analytical tools that will help
to test the epigenetic theory.” He suggests
that more emphasis is needed on studying
non-Mendelian processes in diseases such
as schizophrenia, asthma, multiple sclero-
sis, and diabetes.
The past decade has also been produc-
tive in developing strong links between
aberrant DNA methylation and aging, says
Jean-Pierre Issa, a professor of medicine at
The University of Texas M.D. Anderson
Cancer Center. He presented information
on aging and epigenetic effects at a
November 2005 conference titled “Envi-
ronmental Epigenomics, Imprinting, and
Disease Susceptibility,” held in Durham,
North Carolina, and sponsored in part by
the NIEHS. Some of the strongest, decade-
old evidence shows progressive increases in
DNA methylation in aging colon tissues,
and more recent evidence links hyperme-
thylation with atherosclerosis. Altered, age-
related methylation has also been found in
tissues in the stomach, esophagus, liver,
kidney, and bladder, as well as the tissue
types studied by Esteller. Much of Issas
current work focuses on the links between
epigenetic processes, aging, the environ-
ment, and cancer, and possible ways to
therapeutically reverse methylation linked
with cancer.
Current and Future Quandaries
The accumulated evidence indicates that
many genes, diseases, and environmental
substances are part of the epigenetics pic-
ture. However, the evidence is still far too
thin to form a basis for any overarching
theories about which substances and
which target genes are most likely to
mediate adverse effects of the environ-
ment on diseases, says Melanie Ehrlich, a
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Randy Jirtle
Epigenetics: The Science of Change
A pup of a different color. Supplementation of maternal diet with genistein and other compounds
induced alterations in DNA methylation that were reflected in offspring coat color changes.
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VOLUME 114 | NUMBER 3 | March 2006
A 165
biochemistry professor at the Tulane
University School of Medicine and Tulane
Cancer Center who has been conducting
research on the topic for more than two
That sense of uncertainty generally
leaves epigenetics out of the regulatory pic-
ture. “It’s [too early] to actually use it at
the moment,” says Julian Preston, acting
associate director for health at the EPAs
National Health and Environmental Ef-
fects Research Laboratory. But Preston says
the agency already relies more on its
improving understanding of mechanistic
processes, including epigenetics, and there
is a clear effort within the EPA to expand
genomics efforts both within the agency
and with others with whom the agency
At the FDA, scientists are investigating
many drugs that function through epige-
netic mechanisms (although as spokes-
woman Christine Parker notes, the agency
bases its approvals on results of clinical tri-
als, not consideration of the mechanism by
which a drug works). One such drug, azac-
itidine, has been approved for use in the
United States to treat myelodysplastic syn-
drome, a blood disease that can progress to
leukemia. The drug turns on genes that
had been shut off by methylation. The
drug’s epigenetic function doesnt make it a
miracle drug,” however. Trials indicate it
benefits only 15% of those who take it,
and a high percentage of people suffer seri-
ous side effects, including nausea (71%),
anemia (70%), vomiting (54%), and fever
Ehrlich points out that azacitidine also
has effects at the molecular level—such as
inhibiting DNA replication and apopto-
sis—that may be part of its therapeutic
benefits. The drugs mixed results might
also be explained in part by a study pub-
lished in the October 2004 issue of
by Andrew Feinberg, director of the
Johns Hopkins University Center for
Epigenetics in Common Human Disease,
and his colleagues. They found that each of
two tested drugs, trichostatin A and 5-
aza-2´-deoxycytidine (which is related to
azacitidine), can turn on hundreds of genes
while also turning off hundreds of others.
If that finding holds in other studies, it
suggests one key reason why it is so diffi-
cult to create a drug that doesnt cause
unintended side effects.
Public and Private
Despite the potentially huge role that epi-
genetics may play in human disease, invest-
ment in this area of study remains tiny
compared to that devoted to traditional
Matt Ray/EHP
Epigenetics: The Science of Change
n December 2005 a group of 40
international scientists publicly
proposed a U.S. Human Epigen-
ome Project to complement a
European project of the same
name launched in 2003. Group
member Andrew Feinberg, a
geneticist at the Johns Hopkins
University School of
Medicine, says, “We’re
hoping to see how this
idea takes hold. There
is this ocean of infor-
mation that is largely
The goal of the
U.S. project will be to
comprehensively map
methylation and his-
tone modifications
—the two main class-
es of epigenetic mod-
ifications—in a diverse
set of normal tissues.
These epigenomes
would then serve as
a reference for com-
parison with diseased
tissues, revealing epi-
genetic causes of dis-
ease. Project organizers are now
compiling a detailed proposal, with
budget estimates and a timeline.
Although both the U.S. and
European projects ultimately aim
to map all genes, the U.S. effort
will look at different tissue and
cell types than the European
effort, and will also look at model
organisms like yeast and the fly.
The two groups are already work-
ing closely together in planning
their projects to avoid redundan-
cies, and this cooperation will
likely continue.
Understanding cancer would
be one long-term goal for the U.S.
project, but epigenetics—changes
in gene expression heritable from
cell to daughter cell without
changes in DNA sequence—tran-
scends any one disease. “It has
profound implications in aging,
neurological disorders,
and child develop-
ment,” says Peter
Jones, another group
member and director
of the Norris Compre-
hensive Cancer Center
at the University of
Southern California.
Jones and his col-
leagues argue that
the importance
of epi-
genetics in human dis-
ease, together with
the maturing of tech-
nologies for mapping
epigenetic changes,
make a human epi-
genome project both
critical and feasible.
Epigenetics, says
cancer biologist Jean-
Pierre Issa of The University of
Texas M.D. Anderson Cancer Center,
could prove more important than
genetics for understanding envi-
ronmental causes of disease.
“Cancer, atherosclerosis, Alzheim-
er’s disease [are all] acquired dis-
eases where the environment very
likely plays an important role,” he
points out. “And there’s much
more potential for the epi-
genome to be affected . . . than
the genome itself. It’s just more
fluid and more easy to be the cul-
prit.” Ken Garber
U.S. Human Epigenome Project
genetics work. Several efforts to change
that are under way.
In Europe, the Human Epigenome
Project was officially launched in 2003 by
the Wellcome Trust Sanger Institute,
Epigenomics AG, and the Centre National
de Génotypage. The groups focus is on
DNA methylation research tied to chro-
mosomes 6, 13, 20, and 22. They may be
joined soon by organizations in Germany
and India, where scientists plan to work on
chromosomes 21 and X, respectively, says
Sanger senior investigator Stephan Beck.
But comprehensively studying all the
epigenetic and epigenomic factors related
to a multitude of diseases and health con-
ditions will take much more work. “A
[comprehensive] Human Epigenome
Project is a lot more complicated than a
Human Genome Project,” Jones says.
“There’s only one genome, [but] an epi-
genome varies in each and every tissue.”
The Human Genome Project was a world-
wide effort that took more than a decade
and billions of dollars to complete.
Jones and Robert Martienssen ad-
dressed some of the complexities of a com-
prehensive, worldwide Human Epigenome
Project in the 15 December 2005 issue of
Cancer Research
. Reporting on a June 2005
workshop convened by the American
Association for Cancer Research, they con-
cluded that, despite all the looming diffi-
culties, such a project is essential, and the
technology is sufficiently advanced to
“I think it’s going to happen a lot soon-
er than I thought just a year or so ago,” Jirtle
says. A group of researchers has already start-
ed the footwork to launch a U.S. comple-
ment to the European Human Epigenome
Project effort [see box, p. A165].
Other efforts are gaining ground.
Another European group, the Epigenome
Network of Excellence, took off in June
2004. This information exchange network
includes members in the public and pri-
vate sectors spread throughout ten Western
European countries. Their objectives are to
coordinate research, provide mentors, and
encourage dialogue via their website. And
in Asia, a conference held 7–10 November
2005 in Tokyo, “Genome-Wide Epigen-
etics 2005,” was dedicated in large part to
facilitating a coordinated epigenomics
research effort in Japan and possibly all of
Asia, says Ushijima, one of the conferences
In the United States, the National
Cancer Institute and the National Human
Genome Research Institute formally kicked
off a major effort 13 December 2005 that
will include epigenomic work. The pilot
project of The Cancer Genome Atlas, fund-
ed by $50 million each from the two insti-
tutes, is designed to lay the groundwork for
comprehensive study of genomic factors
related to human cancer. The initial three-
year effort is expected to focus on just two
or three of the more than 200 cancers
known to exist, but if its successful in
developing methods and technologies, the
number of cancers evaluated could then
expand. If a high number of cancer genes
are eventually scrutinized, the effort would
be the equivalent of thousands of Human
Genome Projects.
To help push the boundaries further, the
NIEHS and the National Cancer Institute
are in the midst of awarding grants totaling
$3.75 million to study a wide range of epi-
genetic topics, such as identification of
high-risk populations, dietary influences
on cancer, and detailed study of numerous
specific mechanisms linking environmental
agents with epigenetic mechanisms and
resulting disease. The dozen or so recipi-
ents are expected to launch their projects
by fall 2006.
The NIEHS has also begun to integrate
epigenomics projects into its research port-
folio over the past five to six years. “Its an
emerging area thats very important,” says
Frederick Tyson, a program administrator
in the NIEHS Division of Extramural
Research and Training. And epigenetics is
likely to be one of the half dozen or so most
important considerations as NIEHS pro-
ceeds with its Environmental Genome
Project, according to institute director
David Schwartz.
The DNA Methylation Society, a pro-
fessional group, has been growing slowly
but steadily over the past decade, says
founder and current vice president Ehrlich.
As part of its efforts, the society launched a
, in January 2006 with
the goal of covering a full spectrum of epi-
genetic considerations—medical, nutri-
tional, psychological, behavioral—in any
organism. Such groups are a valuable rally-
ing point for this field, Jirtle says. He him-
self slowly worked his way into epigenetics
from an initial cancer focus, and his segue
is typical of many. “If you study epigenet-
ics, you dont have a home; we come from
all different fields,” he says.
Interest in the private sector is also pick-
ing up. For instance, Epigenomics AG, with
offices in Berlin and Seattle, is working on
early detection and diagnosis of cancer and
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Epigenetics: The Science of Change
Professional Organizations and Projects
DNA Methylation Society (international)
Epigenome Network of Excellence (Europe)
Human Epigenome Project (Europe)
DNA Methylation Database
Imprinted Gene Databases
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A 167
endometriosis (for which there is limited
evidence of an epigenetic component), as
well as development of products to predict
effectiveness of drugs to treat these diseases.
Founded in 1998, and now with about 150
employees, the company is focusing on
DNA methylation mechanisms, and is
working with companies such as Abbott
Laboratories, Johnson & Johnson, Philip
Morris, Roche Diagnostics, Pfizer, and
AstraZeneca. CEO Oliver Schacht says the
surging interest in this field is typified by
the difference between the 2004 American
Association for Cancer Research confer-
ence, which had half a dozen or so talks or
posters on epigenetics, and the 2005 event,
which had about 200.
Tool Time
If epigenetic work is to continue breaking
new ground, many observers say technolo-
gy will need to continue advancing. Jones
and Martienssen note in their paper that
there must be additional improvements in
high-throughput technologies, analytical
techniques, computational capability,
mechanistic studies, and bioinformatic
strategies. They also say there is a need for
basics such as standardized reagents and a
consistent supply of antibodies for testing.
Preston agrees with many of these ideas,
and says there is also a need to develop a
comprehensive tally of all proteins in the
cell and to get better protein modification
information. He says universities are recog-
nizing the demand for the talents needed to
solve epigenomics problems, and are
increasing their efforts to cover these topics
in various ways, especially at the graduate
school level.
Other groups are doing their part by
creating tools to further the field. All the
imprinted genes identified so far are tracked
in complementary efforts by Morisons and
Jirtles groups and the Mammalian Genetics
Unit of the U.K. Medical Research Coun-
cil. The European managers of the DNA
Methylation Database have assembled a
compendium of known DNA methylations
that, although not comprehensive, still pro-
vides a useful tool for researchers investigat-
ing the roughly 22,000 human genes.
Kunio Shiota, a professor of cellular
biochemistry at the University of Tokyo
and one of the co-organizers of the
November 2005 Tokyo conference, says
epigenetic advances will rely in part on a
range of processes that are slowly becoming
familiar to more researchers—massively
parallel signature sequencing (MPSS),
chromatin immunoprecipitation microar-
ray analysis (ChIP-chip), DNA adenine
methyltransferase identification (Dam-ID),
protein binding microarrays (PBM), DNA
immunoprecipitation microarray analysis
(DIP-chip), and more. Someday, he says,
these terms could become fully as familiar
as MRI and EKG.
The rapidly growing acceptance of epi-
genetics, a century after it first surfaced, is
a huge step forward, in Jirtles opinion.
“We’ve done virtually nothing so far,” he
says. “I’m biased, but the tip of the iceberg
is genomics and single-nucleotide poly-
morphisms. The bottom of the iceberg is
Bob Weinhold
Epigenetics: The Science of Change
... Currently, a plethora of diseases, behaviours, and various health indicators have been associated with one or more epigenetic mechanisms [31]. Diseases such as cancers, cognitive dysfunction, and respiratory, metabolic syndromes, cardiovascular and renal diseases, autoimmune diseases or neuro-cognitive illness are mostly known to be linked with epigenetic regulation [32]. In its literal sense, the term "epigenetic" means "in addition to alterations in genetic sequence." ...
... Aforementioned post-translational modification, particularly those of histone proteins, manifest as remodelling of chromatin and RNA-based mechanisms to cause their effects in an organism [34]. Although it is known that epigenetic processes happen naturally and are essential to many aspects of organismal function, when they go wrong they can have serious negative impacts on both health and behaviour [32]. Perhaps the most well-known epigenetic activity is cytosine methylation, or the insertion of a methyl group (CH3), most frequently where cytosine bases occur consecutively. ...
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The scale at which the SARS-CoV-2/COVID-19 pandemic has spread remains enormous. Provided the genetic makeup of the virus and humans is readily available, the quest for knowing the mechanism and epidemiology continues to prevail across the entire scientific community. Several aspects, including immunology, molecular biology, and host-pathogen interaction, are continuously being dug into for preparing the human race for future pandemics. The exact reasons for vast differences in symptoms, pathophysiological implications of COVID-infections, and mortality differences remain elusive. Hence, researchers are also looking beyond traditional genomics, proteomics, and transcriptomics approach, especially entrusting the environmental regulation of the genetic landscape of COVID–human interactions. In line with these questions lies a critical process called epigenetics. The epigenetic perturbations in both host and parasites are a matter of great interest to unravel the disparities in COVID-19 mortalities and pathology. This review provides a deeper insight into current research on the epigenetic landscape of SARS-CoV-2 infection in humans and potential targets for augmenting the ongoing investigation. It also explores the potential targets, pathways, and networks associated with the epigenetic regulation of processes involved in SARS-CoV-2 pathology.
... Epigenetic engineering technologies make it experimentally possible to modify individual chromatin marks (sites where DNA methylation, small interfering RNA, or histone variants are associated with an epigenetic event) at specific user-defined sites (Margueron and Reinberg 2010;Köferle et al. 2015). Epigenetic processes change the activity of genes without changing a DNA sequence, but still leads to modifications that can be transmitted to daughter cells (although some epigenetic changes can be reversed) (Weinhold 2006). Epigenetic processes can occur through DNA methylation, acetylation, phosphorylation, ubiquitylation, and sumolyation. ...
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Plant breeding has been closely aligned with the development of civilisations and continues to be important for the supply of nutritious food and a key factor in reducing poverty and hunger. Plant breeding uses a range of techniques for both expanding and exploiting the genetic potential of plants. However, some techniques are deemed higher risk than others despite the end products of both processes at times being indistinguishable. While it is considered that the domestication of some plant species began over 10,000 years ago, it is only in the last 100 years or so that modern plant breeding has been used to develop thousands of cultivars in a range of plant species for food, feed, and recreation. In the last 25 years, genetic modification and, more recently, New Breeding Technologies have been used to introduce new variations into important plant species. This has resulted in mistrust and suspicion, and a range of regulatory systems. Product-based and process-based regulatory systems differ in the information required for decision-making. Methods used for the development and manipulation of plant traits are reviewed in an attempt to understand the reasons why some are deemed more acceptable than others. ARTICLE HISTORY
... He described them as "genetic elements," wherein the chromosomes influence numerous attributes simultaneously impacting the phenotypes. 4 Several different studies in recent decades had proved that the biological and physical processes involved in each organism, from birth to death were regulated by epigenetic systems. 5 Furthermore, DNA methylation alterations increase tumor suppressor gene expression while reducing the synthesis of oncogenes. ...
... These results may lay the groundwork for understanding mechanisms underlying the association of vitamin D and the pain experience. Epigenetics is being studied in a variety of health outcomes [21]. Epigenetic control of gene expression is normal and natural, but some epigenetic changes can lead to detrimental behavioral and health outcomes to the organism. ...
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Context: Recent evidence suggests that Vitamin D may interact with the epigenome and play a role in the pain experience. In order for proper functioning to occur, there must be an adequate level of Vitamin D present, made possible by enzymatic reactions that allow Vitamin D to be biologically active. The purpose of this study was to explore the epigenetic landscape of genes involved in Vitamin D metabolism in individuals with and without chronic knee pain. Procedures: Community-dwelling individuals recruited as part of a larger study focused on knee pain provided demographic, clinical and pain-related information, as well as an intravenous blood sample to determine DNA methylation levels at CpG sites. Main findings: There were differences in DNA methylation between those with and without pain in genes that code for enzymes related to Vitamin D metabolism: CYP24A1 (24-hydroxylase) and CYP27B1 (1--hydroxylase). There was also hypermethylation on the gene that codes for the Vitamin D receptor (VDR). Principal conclusions: The presence of chronic pain is associated with epigenetic modifications in genes responsible for the expression of enzymes involved in Vitamin D metabolism and cellular function. These results lay groundwork in understanding the mechanism underlying the association between Vitamin D and chronic pain.
... A pesar de esto, la proporción de estudiantes de posgrado que afirman saberlo es casi cuatro veces mayor a la proporción de estudiantes de secundaria que respondieron lo mismo. Esto se puede deber a que es una ciencia emergente de la cual se está empezando a hablar y considerar en los medios de comunicación (Weinhold, 2006). ...
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El libro se conforma por 4 capítulos: Pandillas Kids, Pandillas Juvenil, Medio Superior y Superior, y en esta ocasión por el motivo de la celebración de los 20 años de Expociencias se incluye un artículo al principio del Maestro Jorge Álvaro Cerón Hernández de Expociencias Bajío A.C. en el que se hace un análisis de la trascendencia de Expociencias concluyendo que el trabajo se que se ha desarrollado a lo largo de estos años es el impulso al desarrollo de proyectos científicos y tecnológicos juveniles que procuran ofrecer soluciones a problemáticas sociales en un contexto de aprendizaje combinado y por ende formativo, lo que significa trascender en el desarrollo científico de alto impacto. El último capítulo corresponde a la categoría de Nivel Superior, donde los jóvenes universitarios demuestran una vez más que no tienen límites en su creatividad y generación de ideas, exponiendo proyectos que son desarrollos tecnológicos, análisis especializados en proteínas, divulgación de la ciencia, prevención del suicidio juvenil, tecnología de agua, sustentabilidad alimentaria, entre otros temas de gran interés.
The epigenome consists of all the epigenetic alterations like DNA methylation, the histone modifications and non-coding RNAs which change the gene expression and have a role in diseases like cancer and other processes. Epigenetic modifications can control gene expression through variable gene activity at various levels which affects various cellular phenomenon such as cell differentiations, variability, morphogenesis, and the adaptability of an organism. Various factors such as food, pollutants, drugs, stress etc., impact the epigenome. Epigenetic mechanisms mainly involve various post-translational alteration of histones and DNA methylation. Numerous methods have been utilized to study these epigenetic marks. Various histone modifications and binding of histone modifier proteins can be analyzed using chromatin immunoprecipitation (ChIP) which is one of broadly utilized method. Other modified forms of the ChIP have been developed such as reverse chromatin immunoprecipitation (R-ChIP); sequential ChIP (ChIP-re-ChIP) and some high-throughput modified forms of ChIP such as ChIP-seq and ChIP-on-chip. Another epigenetic mechanism is DNA methylation, in which DNA methyltransferases (DNMTs) add a methyl group to the C-5 position of the cytosine. Bisulfite sequencing is the oldest and usually utilized method to measure the DNA methylation status. Other techniques have been established are whole genome bisulfite sequencing (WGBS), methylated DNA immune-precipitation based methods (MeDIP), methylation sensitive restriction enzyme digestion followed by sequencing (MRE-seq) and methylation BeadChip to study the methylome. This chapter briefly discusses the key principles and methods used to study epigenetics in health and disease conditions.
Aging is one of the most complex and irreversible health conditions characterized by continuous decline in physical/mental activities that eventually poses an increased risk of several diseases and ultimately death. These conditions cannot be ignored by anyone but there are evidences that suggest that exercise, healthy diet and good routines may delay the Aging process significantly. Several studies have demonstrated that Epigenetics plays a key role in Aging and Aging-associated diseases through methylation of DNA, histone modification and non-coding RNA (ncRNA). Comprehension and relevant alterations in these epigenetic modifications can lead to new therapeutic avenues of age-delaying contrivances. These processes affect gene transcription, DNA replication and DNA repair, comprehending epigenetics as a key factor in understanding Aging and developing new avenues for delaying Aging, clinical advancements in ameliorating aging-related diseases and rejuvenating health. In the present article, we have described and advocated the epigenetic role in Aging and associated diseases.
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Plants require metals such as copper to survive, but an excess of metals can have phytotoxic effects. The objectives of this study were to (1) analyze the expression of genes associated with copper resistance (RAN1 and MRP4) and (2) assess the effects of copper and potassium ions on global DNA methylation in white spruce (P. glauca). Seedlings were treated with three concentrations of copper sulfate including 1312 mg/kg, 656 mg/kg, and 130 mg/kg. Potassium sulfate and water were used as controls. DNA and RNA were extracted from roots and needles. The levels of gene expression were measured using RT-qPCR and the global 5-methyl cytosine was assessed using the Abcam ELISA kit procedure. Overall, the highest concentration of copper (1312 mg/kg) induced the most severe damages to plants compared to the 656 mg/kg and 130 mg/kg treatments. Copper at the 1312 mg/kg concentration induced an upregulation of the MRP4 gene in roots and needles. The 656 mg/kg and 130 mg /kg of copper induced no significant difference in MRP4 expression compared to the controls. An upregulation of the RAN1 gene was observed only in roots treated with the 1312 mg/kg. This suggests that the amounts of bioavailable copper in mining sites in Northern Ontario cannot induce changes in MRP4 and RAN1 expressions. Differential expressions of RAN1 and MRP4 genes were observed in roots of copper-resistant and copper-susceptible genotypes. An increase of MRP4 gene expression also observed in the resistant and susceptible genotypes compared to the water control. Copper did not induce changes in the level of global cytosine methylation. However, the potassium ions used as control induced a hypomethylation of DNA at the 1312 mg/kg concentration.
Background: Fibrinogen plays an essential role in blood coagulation and inflammation. Circulating fibrinogen levels may be determined by inter-individual differences in DNA methylation at CpG sites, and vice versa. Methods: We performed an epigenome-wide association study (EWAS) of circulating fibrinogen levels in 18,037 White, Black, American Indian, and Hispanic participants representing 14 studies from the CHARGE consortium. Circulating leukocyte DNA methylation was measured in 12,904 participants using the Illumina 450K array, and in 5,133 participants using the EPIC array. Each study performed an EWAS of fibrinogen using linear mixed models adjusted for potential confounders. Study-specific results were combined using array-specific meta-analysis, followed by cross-replication of epigenome-wide significant associations. We compared models with and without C-reactive protein (CRP) adjustment to examine the role of inflammation. Results: We identified 208 and 87 significant CpG sites associated with fibrinogen from the 450K (p-value<1.03×10-7) and EPIC arrays (p-value<5.78×10-8), respectively. There were 78 associations from the 450K array that replicated in the EPIC array and 26 vice versa. After accounting for the overlapping sites, there were 83 replicated CpG sites located in 61 loci, of which only 4 have been previously reported for fibrinogen. Examples of genes located near these CpG sites were SOCS3 and AIM2, which are involved in inflammatory pathways. The associations for all 83 replicated CpG sites were attenuated after CRP adjustment, although many remained significant. Conclusion: We identified 83 CpG sites associated with circulating fibrinogen levels. These associations are partially driven by inflammatory pathways shared by both fibrinogen and CRP.
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