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TBM ESSAY
The dynamic epigenome and its implications for behavioral
interventions: a role for epigenetics to inform disorder
prevention and health promotion
Moshe Szyf, Ph.D. ,
1
Yi-Yang Tang, Ph.D.,
2
Karl G. Hill, Ph.D.,
3
Rashelle Musci, Ph.D.
4
Abstract
The emerging field of behavioral epigenetics is producing
a growing body of evidence that early life experience and
social exposure can alter the way by which genes are
marked with DNA methylation. We hypothesize that
changes in DNA methylation as well as other epigenetic
markers could generate stable phenotypes. Early life
adversity appears to result in altered DNA methylation of
genes in the brain and peripheral tissues, and these
changes are associated with adverse phenotypic
changes. Although the data are still sparse, early
epigenetic studies have provided a proof of principle that
experiences and the environment leave marks on genes,
and thus suggest molecular and physical mechanisms for
the epidemiological concept of gene-environment
interaction. The main attraction of DNA methylation for
type I (TI) translational prevention science is the fact that,
different from genetic changes that are inherited from our
ancestors, DNA methylation is potentially preventable
and reversible and, therefore, there is a prospect of epi-
genetically targeted interventions. In addition, DNA meth-
ylation markers might provide an objective tool for
assessing effects of early adverse experience on individ-
ual risks as well as providing objective measures of
progress of an intervention. In spite of this great potential
promise of the emerging field of social and translational
epigenetics, many practical challenges remain that must be
addressed before behavioral epigenetics could become
translational epigenetics.
Keywords
DNA methylation, Epigenetics, Early life stress,
Translational science, Interventions, Gene
environment, Transgenerational, Prevention science
INTRODUCTION
The understanding that behavior and human mental
activity are tied to gene function has important impli-
cations for understanding not only neuropsychiatric
disease but also the natural variation in social and
intellectual achievements of humans. Animal studies
have identified genes that influence animal behavior,
and human genome-wide association studies
(GWASs) have linked certain neuropsychiatric dis-
eases to interindividual differences in sequences of
genes [1–3]. Moreover, certain common differences
in genetic sequences were associated with human be-
havioral phenotypes such as anxiety [4], stress [5], and
aggression [6]. However, although GWASs were able
to associate several genetic differences in people with
behavioral disorders and neuropsychiatric disease, the
effects in most cases are small and explain only a small
fraction of the interindividual variation in the popula-
tion. It is possible that the missing explanation resides
in the fact that variations in these phenotypes are
determined by sequence differences in a combination
of a large number of genes. An additional possible
mechanism is that other factors are critical in stable
programming of gene function involved in human
behavior. The fundamental questions are how much
of our behavior is predetermined exclusively by ge-
netic sequences and thus resilient to interventions and
whether there are other factors that influence interin-
dividual differences in stable gene programs which
could be altered by interventions. The answer to these
long-standing questions has wide-ranging implications
not only to the quest for understanding fundamental
biological and pathological mechanisms but also to
almost all areas of human activity from medicine to
education, politics, and social policy.
The idea that the relationship between genotype
and phenotype is not always directly immediate has
been noted in the previous century by Waddington
who was trying to understand how one genome could
encode the multiple phenotypes of a multicellular
1
Department of Pharmacology and
Therapeutics,
McGill University Medical School,
3655 Sir William Osler Promenade,
Montreal, Quebec, CanadaH3G1Y6
2
Texas Tech University, Lubbock, TX,
USA
3
University of Washington, Seattle,
WA, USA
4
Johns Hopkins University, Baltimore,
MD, USA
Correspondence to: M Szyf
moshe.szyf@mcgill.ca
Cite this as:
TBM
2016;6:55–62
doi: 10.1007/s13142-016-0387-7
Implications
Researchers: provides a review and insight into
the science of epigenetics and its implications in
neuroscience.
Practitioners: introduce the practitioners to impli-
cations of the science of epigenetics on understand-
ing, preventing, and treating behavioral disorders
Policy makers: the implications that epigenetics
has on social policy
TBM page 55 of 62
organisms [7]. Waddington coined the term epigenetics
to describe the mechanisms that are involved in
programming identical genes differently in different
organs during embryogenesis. The biochemical mech-
anisms underlying epigenetic programming have been
elucidated in the last few decades. However, the dom-
inant idea in the field has been that these epigenetic
programs are highly predictable and evolutionarily
programmed during embryogenesis and are driven
by predetermined (innate) driving forces that are fixed
after birth. Are similar mechanisms utilized to pro-
gram the genome to respond to external environmental
factors? Could epigenetics confer experiential identity
on DNA in addition to cell type identity? Are the
epigenetic changes in response to the environment
limited to a period after birth or could these be oper-
ative throughout life? Obviously, the answer for this
question has immediate implications for either preven-
tion or intervention.
The question of whether epigenetic mechanisms
could be programmed by external environments has
been a topic of extensive research in the last decade.
The first set of experiments demonstrating postnatal
epigenetic programming by postnatal social environ-
ments was by Weaver et al., who showed that differ-
ences in maternal care in rodents after birth determine
differences in their adult offspring behavior by epige-
netic programming [8]. Importantly, these studies also
showed that programming by maternal care could be
reversed in adulthood by cross-fostering as well as
epigenetic therapeutics [8]. These studies and others
established that epigenetic programs are reset in re-
sponse to external cues including social environments
and, as a result, they define stable phenotypes without
changing the gene sequence. Epigenetic processes pro-
vide experiential identity onto DNA in addition to the
cell type identity. These processes are proposed to be
active during the early life period. However, it is pos-
sible to reverse epigenetic programming later in life
with the appropriate interventions. These studies im-
ply that it should be possible to prevent the emergence
of certain phenotypes by targeting the social environ-
ments that trigger adverse epigenetic programming.
Implications for the role of epigenetics in prevention
research and practice fall into the rubric of type I
translation (see Table 1), which pertains to the devel-
opment of basic science-informed preventive interven-
tions. In this paper, we will discuss epigenetic mecha-
nisms with particular focus on DNA methylation and
address the questions of how epigenetic information
might instruct translational science by providing
mechanistic concepts, diagnostic tools, and guides for
prevention.
EPIGENETIC MECHANISMS
RNA is transcribed from DNA by the cellular tran-
scription machinery which is composed of several
proteins that can read the DNA sequence template
and write or transcribe a chain of RNA bases, a tran-
script. Some transcripts called messenger RNA
Table 1 |Translational research stages
Type Definition
Type 0 translation (T0) The fundamental process of translating findings and discoveries from social and biomedical sciences into research with humansubjects
Type 1 translation (T1) Moving from bench to bedside. Translation of applied theory to methods and program development
Type 2 translation (T2) Moving from bedside to practice and involves translation of program development to implementation
Type 3 translation (T3) Determining whether efficacy and effectiveness trial outcomes can be replicated under real-world settings
Type 4 translation (T4) Wide-scale implementation, adoption, and institutionalization of new guidelines, practices, and policies
Type 5 translation (T5) Translation to global communities. Involves fundamental and universal change in attitudes, policies, and social systems
ESSAY
TBMpage 56 of 62
(mRNA) could be further translated into proteins. An
mRNA transcript is then transported into a different
machinery in the cell that translates the RNA sequence
and assembles, based on the information in the tran-
script, a sequence of amino acids which are the build-
ing blocks of proteins. Proteins are responsible for
both the structure as well as the Bworkings^of our
body. A genetic change in the sequence can change
the identity of the protein produced or change its
activity, and this could result in a change in phenotype.
Epigenetic modifications consist of changes on top of
(epi) the genome but do not change the inherited
genomic structure itself. During the last three decades,
biochemistry has been characterizing several levels of
epigenetic mechanisms. Two ways this modification
commonly occurs include (1) the attachment of a
chemical structure called a methyl group to the back-
bone of a DNA molecule effectively turning off atran-
scription of an associated gene [9,10] or (2) the mod-
ification of the histones around which the DNA is
wrapped, which then affects the accessibility of the
DNA for transcription [11,12]. DNA is packaged in
the nucleus of a cell into a structure termed chromatin.
This structure includes, in addition to DNA, a scaffold
of proteins called histones. Histones are chemically
modified, and the modification of histones determines
the accessibility of genes to the machinery that tran-
scribes genes into RNA. DNA methylation is thought to
be more on/off, while chromatin modification is more
graduated, like a knob ratcheting up or down tran-
scription [13]. Epigenetic modification of DNA func-
tioning is a natural process. Epigenetic modification
through exposure to the cellular environment plays a
large role in tissue differentiation during fetal develop-
ment [14]. Evidence has also been growing about the
role of epigenetic modification in response to the social
environment. The lesson that we have learned from
studying DNA methylation patterns in different tissues
is that identical DNAs could have different DNA
methylation patterns and divergent gene expression
programs. Vast phenotypic (including behavioral) dif-
ferences could therefore be expressed by identical
genetic sequences. Phenotypic differences could be
generated by epigenetic rather than inherited genetic
differences. If a similar mechanism operates in people
that were exposed to different environments, then we
have a mechanism explaining how environment could
generate different phenotypes even when the genetic
sequence is identical. This area of research addresses
age-old questions about phenotypic variability given
similar genomic structures and potentially furthers our
understanding of the mechanisms by which environ-
ments alter phenotypic expressions.
DNA methylation and regulation of gene expression
DNA methylation alters the way in which genes ex-
press themselves without inducing change in the actual
sequence of the genes but having functional conse-
quences. The same sequence of DNA could either be
expressed or silenced based on its state of methylation
(Fig. 1). Methylation of critical regulatory regions of
genes can silence gene expression by blocking access
to factors that recruit the transcription machinery that
transcribes the genes [15,16] or through recruitment
of proteins that modify the chromatin and close the
X
DNMT
demethylase
Hydroxylaon TET
Deaminaon AID deaminase
CH3OH OH-
PROTEIN A X
Phenotype A Phenotype B
Fig 1 | DNA methylation and demethylation equilibrium; impact on gene expression and the phenotype. The state of DNA
methylation is a balance of methylation and demethylation. DNA methylation reactions are catalyzed by DNA methyltransferases
(DNMT) which transfer the methyl group from S-adenosylmethionine (SAM)releasingS-adenosylhomocysteine (SAH). Deme-
thylation is catalyzed by a bona fide demethylase which removes a methyl group from DNA which reacts with OH–from water and
is released as methanol (CH
3
OH). Methyl cytosine in critical positions in DNA silences gene transcription (X over green horizontal
arrow), while the unmethylated gene is transcribed (green horizontal arrow). The transcript is translated to protein A which is
responsible for phenotype A. When the gene is methylated, no transcript is produced and no protein is translated, leading to
phenotype B. Alternative mechanisms for demethylation involve either hydroxylation of the methyl group by TET enzymes or
deamination by deaminase enzymes followed with repair
ESSAY
TBM page 57 of 62
chromatin around the gene [17]. Modification of his-
tones determines the accessibility of genes to the ma-
chinery that transcribes genes into RNA. A gene found
in a closed chromatin is inaccessible and silent.
Reversibility of DNA methylation
If DNA methylation plays a role in responding to
experience in fully differentiated tissue, it must be
biochemically reversible. That is, DNA should be ei-
ther methylated or demethylated in response to envi-
ronmental signals. Reversibility of DNA methylation
is also critical for an intervention aimed at resetting
epigenetic programming.
Although the mechanisms responsible for demethy-
lation are yet unclear, there is evidence that DNA
methylation is potentially reversible even in mature
fully differentiated neurons [8,18]. This knowledge
has two important implications for our discussion.
First, DNA methylation could change in adult tissues
and, therefore, even adult tissue should be potentially
responsive to environmental cues and readjustment of
phenotypes could theoretically occur even in adults.
Second, it should be possible to intervene to reverse
DNA methylation and alleviate adverse phenotypes.
Epigenetic programming by early life adversity
It was originally believed that a loss of methyl marks
could occur only when cells divide. During cell divi-
sion, new unmethylated DNA is synthesized; if DNA
methylation is blocked at the time of synthesis, the new
DNAwill be unmethylated. Most neurons in our brain
do not divide. It was therefore believed that DNA
methylation in neurons remains fixed after neurons
mature and that changes in DNA methylation were
unlikely to occur in the brain. The reversibility of
DNA methylation suggests that DNA methylation
changes may be feasible in cells that do not divide,
such as neurons. The fact that the biochemistry is
consistent with changes in DNA methylation even
after embryonal development is completed opens up
the opportunity for additional changes in DNA meth-
ylation in mature cells that would affect the phenotype.
Cues triggering such changes could come from the
environment. It is conceivable that chemical expo-
sures could alter DNA methylation by interacting with
the enzymes that either methylate or demethylate
DNA. A more challenging hypothesis, however, is that
changes in DNA methylation could be brought about
in response to social exposures.
The first evidence that social exposure could alter
DNA methylation in the brain came from studies on
maternal care in rats [8]. The postnatal mother-
neonate interaction is the earliest social environment
encountered by the developing mammal, and it plays
an important role in determining its future health. In
rodents, maternal care involves pup licking and
grooming (LG) by the mother. Pups that experience
high intensity of maternal LG develop into adults that
are less stressed and less anxious than pups that expe-
rience low maternal LG. Interestingly, the phenotypic
differences between offspring of high and low LG are
not genetic and are not inherited from the biological
mother through germline transmission (the maternal
egg that formed the offspring); cross-fostering experi-
ments demonstrate that the stress responsivity and
anxiety phenotype of the low-LG offspring are trans-
mitted by the fostering mother [8,19]. In addition to
the stressand anxiety phenotype, the mother transmits
her nurturing behavior to her female offspring [19].
The low/high LG stress and anxiety phenotypes are
behaviorally transmitted across multiple generations
since female offspring of low-LG mothers develops
into low-LG mothers and offspring of high-LG moth-
ers develops into high-LG mothers and sire high-LG
offspring. This serves as a perfect example of the
impact that a postnatal social environment has on the
establishment of stable phenotypes that are socially
inherited. This study also illustrates that early life
interventions such as cross-fostering [19] could pre-
vent the development of adverse phenotypes and
block their transgenerational transmission. It should
be noted here that that there are two phenotypic out-
comes potentially affected. First is the impact on the
offspring’s overall predisposition or behavior (stress/
anxiety, aggression, etc.) that could possibly be epige-
netically transmitted. And second, that the actual be-
havior of the parent could be transmitted to the off-
spring (e.g., nurturance). It stands to reason that this
response is not limited to cross-fostering and to rodents
only and that other early life interventions in humans
such as parent training [20,21] could have a similar
impact (see Fig. 2).
What is the mechanism that mediates the long-term
effects of parental care and other early life experien-
ces? Understanding these mechanisms is critical for
developing more targeted preventive and intervention
strategies as well as for identifying people at risk of
developing adverse phenotypes later in life. Weaver
et al. focused on the glucocorticoid receptor (nr3c1)
gene in the hippocampus, a nodal point of negative
feedback regulation of the hypothalamic-pituitary-
adrenal (HPA) axis and stress. Weaver et al. demon-
strated a higher level of DNA methylation in adult
offspring of the low LG in the CG dinucleotide se-
quence sitein the nr3c1 gene contained in the sequence
that binds the transcription factor NGFIA, a transcrip-
tion factor that activates the nr3c1 gene [8]. The differ-
ence in DNA methylation emerged after birth concur-
rently with the exposure of the pups to maternal lick-
ing and grooming, remained into adulthood, and was
transmitted by the fostering mother and not the bio-
logical mother in cross-fostering experiments [8].
These studies provided the first evidence that social
exposure results in a change in DNA methylation in a
critical gene that acts in the brain. Moreover, this
change alters gene expression of a gene with a key role
in regulating the body’s stress response, establishing a
stable phenotype of heightened stress responsivity.
Multigenerational transmission of phenotypes trig-
gered by parental behavior and mediated by DNA
methylation in the offspring could explain gamete-
independent (unrelated to inherited genetic material)
ESSAY
TBMpage 58 of 62
multigenerational transmission of other behaviors
such as risk taking or impulsivity (see Fig. 2).
In summary, these results serve as a paradigm for
other adverse as well as positive social exposures early
in life, providing a proof of principle that (1) adverse
environments in the early life period change the chem-
ical properties of gene modifications and their mode of
action resulting in a long-term phenotypic impact and
(2) altering an adverse environment in very early life
could prevent emergence of adverse phenotypes. This
has obviously important implications for translational
science in humans. An important caveat should be
mentioned here, however, which is that the responses
of DNA methylation to adverse experience early in
life might also be adaptive by preparing the offspring
to an anticipated harsher environment; the context in
many respects determines whether the response is
pathological or functional. Such adaptive processes could
turn maladaptive when the experienced environment
later in life is inconsistent with the anticipated environ-
ment early in life.
The breadth and scope of DNA methylation changes driven by
early life experience
The experiments described above focused on candi-
date genes, candidate physiological pathways, and
candidate brain regions. The question, nevertheless,
remains whether the response to early life adversity is
limited to just classical stress pathways. It is well
known from human studies that early life adversity
impacts several physiological systems in adults and
has broad and varied effects on human health [22,
23]. Differences in maternal care also affect the expres-
sion of hundreds of genes in the hippocampus, sug-
gesting a broad response of the DNA to early life
experience [18]. DNA methylation and chromatin
changes affect broad genomic regions [24]. For exam-
ple, McGowan et al. showed that a large gene cluster
containing the entire family of the protocadherin genes
(associated with many neurodevelopmental processes
like axon guidance and dendrite branching) is epige-
netically programmed by maternal care; the entire
cluster exhibited reduced expression, increased DNA
methylation, and altered chromatin modification in
low-LG adult offspring [24]. It is tempting to speculate
that these responses evolved to adapt animals to antic-
ipated dynamic challenges in the environment [25].
SYSTEM-WIDE RESPONSES TO EARLY LIFE ADVERSITY IN
NON-HUMAN PRIMATES: IMPLICATIONS FOR TRANSLA-
TIONAL SCIENCE
It is almost impossible to define a causal relationship
between early life adversity and DNA methylation
changesinhumanssincetheDNAmethylation
changes detected might reflect underlying genetic dif-
ferences or past histories of environmental exposures
rather than exposure to early life adversity. Addressing
this question requires a randomized design, but it is
ethically impossible to randomize child adversity in
humans. Nonhuman primates offer the closest model
to humans to address this question. Another critical
question for translation of epigenetic data to human
prevention and intervention studies is the question of
whether informative methylation differences associat-
ed with early life adversity are limited to the brain or
whether they exist in other peripheral tissues as well.
Studies comparing methylation in brain and peripher-
al tissues in rhesus macaque monkeys raised maternal-
ly or with a surrogate/peer-rearing group support the
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Adult Risk taking behavior
Adult Risk taking behavior
Adult Risk taking behavio
r
CH3
CH3
CH3
CH3
Child
Intervention
CH3
CH3
CH3
CH3
CH3
CH3
Grand parent
parent
Great Grand parent risk taking behavior
Fig 2 | Multigenerational gamete-independent transmission ofrisk behavior phenotype. Exposure ofthe grandparent during early
childhood to a risk-taking behavior leads to methylation of critical genes (CH
3
), resulting in a risk-taking behavior phenotype in
the grand parent. The grandparent risk-taking behavior alters the parent DNA methylation, leading to a risk-taking behavior in the
parent. The parent risk-taking behavior triggers change in methylationin his offspring that results in a risk-taking behavior in the
child. Intervention could happen either by protecting the child from parental risk-taking behavior, thus preventing the develop-
ment of risk-taking behavior in the child or using epigenetic therapy or behavioral therapy later in life to reverse the methylation
state responsible for a risk-taking behavior
ESSAY
TBM page 59 of 62
hypothesis that the response to maternal care is not
limited to one tissue or one brain region but that it is
system wide as well as genome wide [26]. The data are
consistent with the idea that the phenotypic impact of
early life adversity is not limited to the brain and
involves other tissues such as the immune system
[27]. These data also provide a proof of principle for
the feasibility of studying the epigenetic consequences
of social exposures in peripheral Tcells which should
have important implications for translational science.
Reversibility of epigenetic programming by early life adversity
Phenotypes fixed by epigenetic changes are potentially
biochemically reversible [28]. Is it possible to reverse
early life adversity-programmed epigenetic alterations
later in life? This question is critical for translational
science and for translating epigenetic concepts to inter-
ventions in humans. It has been proposed that DNA
methylation is a reversible biological signal [28]. Several
biochemical mechanisms were proposed to be involved
in active DNA demethylation that does not require
DNA synthesis [29–31]. Weaver et al. [8,18]showed
that differences in rat licking and grooming of pups
resulted in differences in methylation of a gene related
to HPA responses to stress in the pups and that this
epigenetic modification was reversible by cross-
fostering and epigenetic therapeutics in adult animals
[8,18]. It was shown that a DNA demethylation inhib-
itor reprogrammed cocaine addiction in a rat model of
cocaine craving [32]. These data provide a proof of
principle for the reversibility of phenotypic changes
triggered by experience-driven epigenetic program-
ming. It is consistent with the idea that the changes that
define the phenotype are not caused only by inherited
genetic polymorphisms but also by reversible epigenetic
marks such as DNA methylation. The remaining chal-
lenge is to determine whether these conclusions could be
translated to humans and whether behavioral interven-
tions could substitute for pharmacological interventions
(for a recent review of epigenetic approaches that target
brain functions, see [33]).
TRANSLATION TO HUMANS; EVIDENCE FOR EPIGENETIC
CONSEQUENCES OF EARLY LIFE ADVERSITY IN HUMANS
Establishing causal relationship between early life ad-
versity and offspring phenotypes in humans in the
same way that it is done in animals is much more
challenging. The first line of evidence in humans for
DNA methylation differences associated with adversi-
ty came from examining postmortem hippocampi of
humans who experienced adverse experiences in
childhood and controls. McGowan et al. showed that
the adult suicide victims who experienced childhood
abuse had higher overall methylation in their ribosom-
al RNA (rRNA) genes and NR3C1 gene and expressed
less rRNA and NR3C1 mRNA [34]. These data were
the first demonstration of evolutionary conservation of
the epigenetic responses to early life experiences.
As discussed above, the changes in DNA methyla-
tion in rodents and monkeys are broad and clustered
and are not limited to one gene. Remarkably, Suder-
man et al. showed that the response in human brains to
early life experience is broad as it is in rats and
monkeys and is evolutionary conserved with a striking
overall similarity between rat and human brains [35].
The PROTOCADHERIN gene family cluster which
showed cluster-wide DNA methylation differences be-
tween high- and low-LG offspring adult rats [24]is
differentially methylated between adult humans who
were abused as children and control adults as well [35].
This evolutionary conservation of the epigenetic re-
sponse of the same cluster of a gene family presents a
strong argument that early life experience alters epige-
netic programming in the brain in humans.
SUMMARY AND PROSPECTIVE
Epigenetic studies in animals have provided evidence
that early life experiences and adversity could stably
affect the phenotype in the absence of genetic differ-
ence. They also provided evidence that prevention of
early life adversities would prevent the development
of adverse phenotypes later in life. Moreover, there is
evidence from animal experiments that phenotypes
that were epigenetically programmed by early life
adversity could be reversed by epigenetic therapeutics
[8,18]. This suggests that it might be possible not only
to prevent but also to reverse the consequences of
early life experiences. Obviously, the most critical
problem with pharmacological approaches is lack of
specificity. An important question is therefore whether
behavioral interventions would be as effective as phar-
macological interventions in reversing epigenetic
programming by early life experience. In addition,
studies in animals and preliminary studies in humans
suggest that DNA methylation markers of early life
adversity might serve as objective diagnostic tools. An
important goal would be to develop early DNA meth-
ylation markers of vulnerability and resilience for be-
havioral disorders later in life.
Many epigenetic challenges remain that need to be
addressed: How can we capture DNA methylation
markers of behavioral disorders before the phenotype
is detected using either prospective or cross-sectional
studies? We need to map the normal longitudinal
trajectories of DNA methylation in human peripheral
cells that could serve as bookmarks for more dedicated
studies. Also needed is to define the temporal order of
early experience, early DNA methylation changes,
late experience, late DNA methylation changes, and
the phenotype. We must further address genetic, eth-
nic, and gender heterogeneity in these responses. A
huge challenge is how do we define causality between
experience, DNA methylation alterations, the role of
these changes in gene programming, and the resulting
behavioral disorders in humans in the absence of a
randomized experimental design? How do we design
epigenetically informed interventions that tap into epi-
genetic mechanisms? What do we do about
ESSAY
TBMpage 60 of 62
transgenerational effects? Is pharmacology an option
when there are no behavioral strategies? How do we
translate new intervention strategies from animal
experiments to humans?
In addition, many critical questions in translational
science remain that must be addressed in properly
designed studies. Could we map DNA methylation
changes early in life that predict risk and resilience and
provide mechanistic insight as well? Does consistent
exposure to positive, supportive environments produce
a methylation pattern that places children on a positive
developmental trajectory, more resilient to subsequent
adversities [36]? Are DNA methylation patterns defined
by early life experience altered with childhood, adoles-
cence, and adult experience and how do these changes
relate to environmental exposures? When is the best
time for intervention? How narrow is the window of
opportunity for prevention? How do we use epigenetic
concepts to design interventions? Prevention research
has shown that early life preventive interventions can
have long-lasting effects on the children into adulthood
[37–40]. Could epigenetic markers be used to follow up
these interventions? Are the critical periods absolutely
critical or could we intervene later in life as well?
The data in humans are still sparse, and none of the
differentially DNA methylation markers described to
date could possibly serve as biomarkers in human
studies. The data to date provide, nevertheless, suffi-
cient justification for integrating DNA methylation
mapping and epigenetic intervention strategies into
our experimental designs. Future studies should focus
on discovery of a panel of DNA methylation-based
biomarkers that could guide epigenetically informed
interventions.
Acknowledgments: The work on this transdisciplinary manuscript resulted
from a National Institute of Nursing Research-funded R13 conference
BAdvancingTransdisciplinary Translation for Prevention of High-Risk Behaviors:
Critical Thinking to Overcome Individual and Institutional Barriers^
(R13NR013623-01-02). Additional support for this paper was provided in part
by a grant from the National Institute on Drug Abuse (R01DA024411 01-06).
The content is solely the responsibility of the authors and does not necessarily
represent the official views of the NINR or NIDA. MS is supported by CIHR-
MOP-42411
Compliance with ethical standardsThe paper is a review article and
discusses published studies. No primary studies with ethics requirements
are discussed.
Conflict of interest: The authors declare that they have no competing
interests.
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