Adelphi University Epigenetics Essay

The main objectives of these assignments are to: 1) encourage you to read papers and grasp

information from outside the textbook, 2) improve your critical thinking and 3) incrementally

improve your written and verbal communication styles of what you learn.

Each summary should have the following five sections:

1. Introduction: State the essential take home message of the assigned paper and what it

is all about. Do not simply restate the abstract.

2. Key points: Describe the main points in the paper

3. Methods/Experiments: Discuss the experiments or methods used to prove these points

(if applicable)

4. Strengths/Weaknesses: Discuss the strengths and weaknesses of the paper. Indicate

additional points of investigation that you think should be pursued and were not

addressed in the paper

5. Conclusion

Epigenetics (21:120:454)
Article Summary – Rubric
Requirement
Introduction
Main points
Experimental approach
Strengths & weaknesses
Conclusion
Excellent Exceeds assignment objectives
Good Meets assignment objectives
20 points
Includes strong thesis statement that
clearly describes the purpose of the
paper.
40 points
Describes the main points of the paper
without including extraneous
information. Doesn’t just repeat what
is stated in the paper but rather
presents these points in an effective
and concise manner.
40 points
Describes in a concise manner but not
in details the main experiments (if
applicable) used. Also, describes the
results of these experiments. Analysis
is comprehensive.
15 points
Thesis statement is clear but not detailed
or descriptive.
10 point
Thesis statement is weak and does not
describe the purpose of the paper.
35 points
Describes the main points of the paper
but includes extraneous information that
are not pivotal.
30 points
Does not describe the main points of the
paper but includes extraneous
information that are not important.
35 points
Describes the main experiments and the
results but does not demonstrate an
understanding of the physiological
significance or the outcomes of these
experiments. Analysis is not
comprehensive or may overlook key
elements.
25 points
Presents some of the strengths and
weaknesses of the paper. Lacks
thoughtful and creative
recommendations for future research.
30 points
Experiments and results are not clearly
described. Lacks a comprehensive
analysis.
15 points
Summary states the concluding thoughts
of the paper.
10 point
Summary lacks key points and insights.
30 points
Presents effectively the main strengths
and weaknesses of the paper and
suggests alternatives to address the
weaknesses. Presents thoughtful and
creative recommendations for future
research.
20 points
Summarizes key points with insights.
1
Poor Assignment objectives minimally met
20 points
Does not identify correctly the main
strengths and weaknesses of the paper. .
Lacks thoughtful and creative
recommendations for future research.
Dr. Rola Bekdash
Rutgers University – Newark
Department of Biological Sciences
Epigenetics (21:120:454)
Article Assignments & Guidelines
I.
Article Assignments
We will discuss five articles this semester. These articles address current topics in the field of
Epigenetics and focus on four main themes such as 1) Epigenetics of stress, 2) epigenetics of
neurodegeneration, 3) epigenetics of mental health and 4) epigenetics of cancer. We will
spend time explaining the main physiological concepts and the experimental approaches used
in investigating the role of epigenetic mechanisms in human health and diseases.
Students are expected to read the assigned articles before coming to class and actively
participate in discussions. You will not receive credit for any missed discussion session. You are
also required to submit on Blackboard by the due date a copy of each paper summary. Your
summary should focus on main points of the assigned article and should be 800 – 1000 words.
You will then receive feedback from your instructor on how to improve the structure of your
summary writing. You are required to resend a revised final version of your summary by the
due date to receive credit. Refer to the “Summary Rubric” that I posted on Blackboard under
“Assignments” to understand how you will be assessed and graded.
II. Papers Summaries
You are required to submit on Blackboard in a docx. File a concise summary (first draft) of
selected articles by the due date. No late submission is allowed.
The main objectives of these assignments are to: 1) encourage you to read papers and grasp
information from outside the textbook, 2) improve your critical thinking and 3) incrementally
improve your written and verbal communication styles of what you learn.
Each summary should have the following five sections:
1. Introduction: State the essential take home message of the assigned paper and what it
is all about. Do not simply restate the abstract.
2. Key points: Describe the main points in the paper
3. Methods/Experiments: Discuss the experiments or methods used to prove these points
(if applicable)
4. Strengths/Weaknesses: Discuss the strengths and weaknesses of the paper. Indicate
additional points of investigation that you think should be pursued and were not
addressed in the paper
5. Conclusion
1
Dr. Rola Bekdash
Write 800 – 1000 words, 11 point Ariel Font, double spaced with one inch margin. After you
receive the instructor’s feedback for improvement, you are required to resubmit a revised
version of your summary on blackboard.
III.
Recitations & Paper Summaries
Useful website: https://learn.genetics.utah.edu/content/epigenetics/
Paper Reference
1
2
3
4
5
Felsenfeld, G. A brief history of epigenetics. Cold Spring Harbor perspectives in
Biology. 1, 6:1 (2014).
https://www.ncbi.nlm.nih.gov/pubmed/24384572
Environmental epigenomics and disease susceptibility. Jirtle & Skinner, 2007.
https://www.ncbi.nlm.nih.gov/pubmed/17363974
Pages 1-5, pages 7-8 and conclusion
Histone methylation versus histone acetylation: new insights into epigenetic
regulation. Rice & Allis. Current Opinion in Cell Biology 2001, 13:263–273.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Histone+methylation+versus
+histone+acetylation%3A+new+insights+into+epigenetic+regulation.
Reversal of maternal programming of stress responses in adult offspring through
methyl supplementation: altering epigenetic marking later in life. Weaver et al.,
2005, J. Neuroscience, 25, 11045-11054.
https://www.ncbi.nlm.nih.gov/pubmed/?term=Reversal+of+maternal+programmin
g+of+stress+responses+in+adult+offspring+through+methyl+supplementation%3A
+altering+epigenetic+marking+later+in+life
Epigenetic mechanisms in neurological and neurodegenerative diseases.
Landgrave-Gomez et al., 2015. Frontiers in Cellular Neuroscience, 9, 1-11.
https://www.ncbi.nlm.nih.gov/pubmed/25774124
Subject to changes with prior notice from the Instructor.
2
REVIEW ARTICLE
CELLULAR NEUROSCIENCE
published: 27 February 2015
doi: 10.3389/fncel.2015.00058
Epigenetic mechanisms in neurological and
neurodegenerative diseases
Jorge Landgrave-Gómez , Octavio Mercado-Gómez and Rosalinda Guevara-Guzmán *
Facultad de Medicina, Departamento de Fisiología, Universidad Nacional Autónoma de México, México, D.F., México
Edited by:
Victoria Campos-Peña, Instituto
Nacional De Neurologia Y
Neurocirugia, Mexico
Reviewed by:
Alexander K. Murashov, East
Carolina University, USA
Jose F. Maya-Vetencourt, Italian
Institute of Technology, Italy
*Correspondence:
Rosalinda Guevara-Guzmán,
Facultad de Medicina,
Departamento de Fisiología,
Universidad Nacional Autónoma de
México, Ave. Universidad # 3000
Col. UNAM Delegación Coyoacán,
Apartado Postal No. 70250, 04510
México, D.F., México
e-mail: rguevara@unam.mx
The role of epigenetic mechanisms in the function and homeostasis of the central nervous
system (CNS) and its regulation in diseases is one of the most interesting processes of
contemporary neuroscience. In the last decade, a growing body of literature suggests that
long-term changes in gene transcription associated with CNS’s regulation and neurological
disorders are mediated via modulation of chromatin structure. “Epigenetics”, introduced
for the first time by Waddington in the early 1940s, has been traditionally referred to
a variety of mechanisms that allow heritable changes in gene expression even in the
absence of DNA mutation. However, new definitions acknowledge that many of these
mechanisms used to perpetuate epigenetic traits in dividing cells are used by neurons
to control a variety of functions dependent on gene expression. Indeed, in the recent
years these mechanisms have shown their importance in the maintenance of a healthy
CNS. Moreover, environmental inputs that have shown effects in CNS diseases, such
as nutrition, that can modulate the concentration of a variety of metabolites such as
acetyl-coenzyme A (acetyl-coA), nicotinamide adenine dinucleotide (NAD+ ) and beta
hydroxybutyrate (β-HB), regulates some of these epigenetic modifications, linking in
a precise way environment with gene expression. This manuscript will portray what
is currently understood about the role of epigenetic mechanisms in the function and
homeostasis of the CNS and their participation in a variety of neurological disorders. We
will discuss how the machinery that controls these modifications plays an important role
in processes involved in neurological disorders such as neurogenesis and cell growth.
Moreover, we will discuss how environmental inputs modulate these modifications
producing metabolic and physiological alterations that could exert beneficial effects on
neurological diseases. Finally, we will highlight possible future directions in the field of
epigenetics and neurological disorders.
Keywords: epigenetics, neurodegeneration, DNA methylation, postranslational modification, Parkinson disease,
epilepsy
EPIGENETICS
The term epigenetics is derived from the theoretical and
experimental work of Conrad Waddington. He coined the
term to describe a conceptual solution to a phenomenon that
arises as a fundamental consideration of developmental biology
(Waddington, 1942). All of the different cells in the body of
one individual have exactly the same genome, that is, exactly
the same DNA nucleotide sequence, with only a few exceptions
in the reproductive, immune and nervous systems. Thus, in
the vast majority of instances, one’s liver cells have exactly
the same DNA as neurons. However, those two types of cells
are clearly vastly different in terms of the gene products that
they produce. Some level of mechanism must exist, Waddington
reasoned, that is “above” the levels of genes encoded by the
DNA sequence, which controls the DNA readout. For this
reason, he defined the term epigenetics in the early 1940s as
“the branch of biology which studies the causal interactions
between genes and their products which bring the phenotype
Frontiers in Cellular Neuroscience
into being” (Waddington, 1968). In the original sense of this
definition, epigenetics is referred to all molecular pathways
modulating the expression of a genotype into a particular
phenotype.
However, and with the fast expansion in this field, epigenetics
has been redefined and accepted today as “the study of changes
in gene function that are mitotically and/or meiotically heritable
and that does not entail a change in DNA sequence.” In this
way, recent advances have evolved our understanding of classical
epigenetic mechanisms and the broader landscape of molecular
interactions and cellular functions that are inextricably linked
to these processes. The current view of epigenetics includes the
dynamic nature of DNA methylation, active mechanisms for DNA
demethylation, differential functions of 5-methylcytosine and
its oxidized derivatives, the intricate regulatory logic of histone
post-translational modifications, the incorporation of histone
variants into chromatin, nucleosome occupancy and dynamics.
Nevertheless, of all these modifications, the mechanisms better
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February 2015 | Volume 9 | Article 58 | 1
Landgrave-Gómez et al.
Epigenetic mechanisms in neurological and neurodegenerative diseases
described in literature generally comprise histone variants,
posttranslational modifications of amino acids on the aminoterminal tail of histones, and covalent modifications of DNA
bases.
In this chapter, we will discuss some of these epigenetic
modifications and how these modifications are associated with
neurologic homeostasis and diseases.
LINKING THE ENVIRONMENT, NUTRITION AND EPIGENETIC
MODIFICATIONS
Although many aspects of nutrition and different kinds of
lifestyles influence metabolic status and disease trajectory
throughout our life, emerging findings suggest that changing
our metabolism with exercise or different dietary regimens such
as ketogenic diets, low-carbohydrate diets, intermittent fasting
or physical exercise can alter the concentration of a variety of
metabolites, some of them capable of modulating the activity of
proteins that elicit epigenetic modifications (Figure 1; Shimazu
et al., 2013; Shyh-Chang et al., 2013).
These epigenetic modifications seem to regulate important
networks of genes mediating physiological processes associated
with the beneficial effect of these diets, providing a rationale
and simple way to prevent or even treat these diseases. Some
reports have shown the efficacy of exercise and diet in cancer;
cardiovascular disease, diabetes, obesity, rheumatoid arthritis
and even in some neurological/neurodegenerative diseases such
as Alzheimer and epilepsy (Müller et al., 2001; Ahmet et al., 2005;
Belkacemi et al., 2012; Kroeger et al., 2012; Lee et al., 2012; Varady
et al., 2013; Colman et al., 2014).
Consistently, some reports have shown that aging it’s a
process that may be altered through some diets, such as calorie
restriction (Colman et al., 2014). The precise mechanisms
of how environment mediates epigenetic modifications are
not clearly understood, however in this manuscript we will
portray some studies that aim to epitomize the relationship
between environment, metabolism, epigenetics and neuro
-logical/neurodegenerative diseases.
EPIGENETIC MODIFICATIONS
Within cell nucleus, the fundamental units of chromatin are
named nucleosomes. Each nucleosome is formed by 147 DNA
base pairs wrapped tightly around an octamer of histone proteins,
which is assembled by two copies of each of the four core histones
(H2A, H2B, H3 and H4). The linker histone H1 binds to the
DNA between the nucleosomal core particles, and their function
is to stabilize higher order chromatin structures. Moreover,
each histone protein consists of a central globular domain
and N-terminal tail that contains multiple sites for potential
modifications (Wang et al., 2013).
In this regard, a variety of different modifications on
amino acid residues of histones have been described. Histone
posttranslational modifications include acetylation, methylation,
phosphorylation, ubiquitination and sumoylation (Table 1;
Sassone-Corsi, 2013).
The principal residues that are substrates of these
modifications are lysine, arginine, serine and threonine amino
acids (Rothbart and Strahl, 2014). These modifications have
been associated to repression or activation of gene transcription
depending on the site of the modification, strongly suggesting the
existence of a histone code. This hypothesis proposes that specific
modifications of histones induce to the interaction with proteins
associated with the chromatin, producing a differential regulatory
response of gene expression (Strahl and Allis, 2000; Table 1 and
Figure 2). These modifications are dynamic in the way that they
are actively added and removed by histone-modifying enzymes
in a site-specific manner, which is essential for coordinated
transcriptional control.
Table 1 | Histone posttranslational modifications and their role on
transcription.
FIGURE 1 | Linking lifestyle with genome expression. DNA and the
proteins that provides chromatin structure are targets of multiple
modifications. In this way, changes in our lifestyle (diets or physical activity)
via the modulation of the metabolism alters the concentration ratio of
different metabolites. The availability and cellular compartamentalization of
these metabolites alters the activity of proteins capable to elicit epigenetic
modifications, contributing to the specificity of the genome expression.
NAD, nicotine adenine dinucleotide (Modified from Sassone-Corsi, 2013).
Frontiers in Cellular Neuroscience
Modification
Role in transcription
Modification site
Acetylation
Activation
Methylation
Activation
Methylation
Repression
Phosphorylation
Activation
H3(K9, K14, K18, K56).
H4(K5, K8, K12, K16).
H2B(K6, K7, K16, K17)
(Strahl and Allis, 2000).
H3(K4me2, K4me3,
K36me3, K79me2)
(Strahl and Allis, 2000)
H3(K9me3, K27me3)
and H4(K20me3)
(Balazs, 2014).
H3(S10)
(Strahl and Allis, 2000)
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Epigenetic mechanisms in neurological and neurodegenerative diseases
HISTONE METHYLATION
Histone methylation is currently associated with multiple
processes such as transcriptional activation and repression,
depending on the modified amino acid residue (Figures 2C,D).
This modification occurs mainly on arginine and lysine residues.
Additionally, these residues could be methylated multiple times
giving different signals depending on how many times the
residue is methylated, making its analysis difficult. In this
regard, current literature has shown that lysine residues can be
methylated even three times; meanwhile, arginine residues can
only be methylated twice (Strahl and Allis, 2000). Furthermore,
there have been some studies associating some processes with
these types of modifications for example H3K4, H3K36 and
H3K79 are associated with chromatin aperture. Nevertheless,
the methylation of these residues has been also associated
with other specific functions. On the other hand, H3K4
trimethylation has been associated with promoter regions. The
monomethylathion of this same residue recruits regulatory
elements that potentiate the promoter activity; such elements are
known as enhancers. Dimethylation of H3K36 has been related
to RNA POL II elongation during transcription (Li et al., 2007).
Also, the dimethylation of H3K79 is particular of promoter
regions stimulating a permissive chromatin for local transcription
(Jacinto et al., 2009). Conversely, the modifications associated
with transcriptional repression are performed on H3K9 and
H3K27 residues (Baylin and Jones, 2011).
FIGURE 2 | Histone posttranslational modifications. (A) Schemes
representing the interaction of the N-terminal dominium of acetylated
histones with the DNA strand (A) and the interaction of a non-acetylated
histone with the DNA strand (B). It can be noticed that acetylated histones
have a minor interaction with DNA strand compared with that of
non-acetylated histones whose positive charges are attracted to negative
charges of DNA. (C) On the other hand different specific marks of
methylation of histone 3 are associated with both transcriptional activation
(C) and repression (D). Also a specific mark of phosphorylation on the (S10)
amino acid of histone 3 has been associated with transcriptional activation
(E) so the lack of this mark may be associated with transcriptional
repression (F).
HISTONE ACETYLATION
The acetylation of histones is a modification associated generally
to transcriptional activity that indicates access of the transcription
machinery to the genes and thus active mechanisms (Strahl
and Allis, 2000; Balazs, 2014). This effect could be explained
by the chemistry of this modification in which an acetyl group
(−COCH3) is incorporated to an amino terminal residue and
thus, the positive charge of histones is reduced, inducing a minor
interaction with DNA resulting in a decrease of the chromatin
compaction (Figures 2A,B; Shahbazian and Grunstein, 2007).
Frontiers in Cellular Neuroscience
DNA METHYLATION
In mammalians, DNA methylation is the covalent union of
methyl groups of cytosines that are found mainly in the context
of dinucleotide 50 -CpG-30 (Figure 3A; Klose and Bird, 2006).
The addition of methyl groups protrudes above the major
groove and when DNA is symmetrically methylated, the methyl
groups promote a conformational change of DNA structure.
The main consequence of methyl modification is that a variety
of transcription factors cannot recognize the DNA and thus
induce repressional transcription (Prokhortchouk and Defossez,
2008).
DNA methylation generates patterns that are established
during embryonic development and such patterns are maintained
by a mechanism when DNA replicates (Figure 3). Interestingly,
these patterns change over time, principally due to environmental
factors (i.e., nutrition, metabolites, exercise, chemical agents)
(Fraga et al., 2005). The mechanism of DNA methylation
is carried out by a set of proteins named DNA methyltransferases (DNMTs). There are two groups of these proteins;
(1) one for de novo methylation; and (2), one for methylation
maintenance. Both enzymes differ depending on the DNA
substrate: for example, maintenance of DNA methylation is
accomplished by DNA methyl transferase 1 (DNMT1). These
proteins add methyl groups to pre-existing methyl patterns on
a new strand of DNA during replication (Figure 3B; Jeltsch,
2006). On the other hand, de novo DNA methylation are
carried out by DNMT3a and DNMT3b. Such proteins are
responsible for the addition of new methyl groups to cytosines
that have not been methylated previously (Goll and Bestor,
2005).
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Epigenetic mechanisms in neurological and neurodegenerative diseases
FIGURE 3 | DNA methylation. Scheme showing the addition of a methyl group on the 5 carbon of cytosine in the context of 50 -CpG-30 dinucleotide (A). The
maintenance of DNA methylation is accomplished by DNA methyl-transferases (DNMT1) when DNA replication occurs (B).
HISTONE VARIANTS
Histone variants such as H2A and H3.3 have been known
since several decades ago and recently, a lot of evidence has
been accumulated about their role in their participation on the
differential structure of chromatin (Henikoff et al., 2004). Among
them, H2A.Z has been located on DNA regions associated with
transcriptional activation, mainly, on promoter regions. This
variant is important because it induces a less stable structure
of chromatin compared with that of the canonical histone H2
(Draker and Cheung, 2009). Another histone variant associated
with promoter regions is H3.3. This variant as well as H2A.Z, is
mainly found on promoter regions suggesting that their structure
promotes the formation of a more permissive chromatin (Jin
et al., 2009).
NEUROEPIGENETICS AND THEIR ROLE IN NEURONAL
FUNCTION
Over the last two decades, the field of epigenetics, particularly
the emerging field of neuroepigenetics, has begun to have a
great impact in different areas such as the study of the CNS
development, learned behavior, neurotoxicology, cognition,
addiction and lately neurological and neurodegenerative
pathology (Sweatt, 2013). In this regard, epigenetics has
undergone an exponential expansion. A quick search of the
PubMed database reveals that about 98% of all the research
work on epigenetics was published within the last 15 years
(Sweatt, 2013). Thanks to these studies, nowadays we know
that either maternal behavior, environmental toxins, nutrition,
physociological or physical stress, learning, drug exposure
or psychotrauma, leads to active regulation of the chemical
and three-dimensional structure of DNA and thus, regulates
epigenetics modifications in the CNS linking environmental
stimuli and gene expression regulation (Tsankova et al., 2007;
Borrelli et al., 2008; Renthal and Nestler, 2008; Champagne and
Curley, 2009; Day and Sweatt, 2010; Dulac, 2010).
These epigenenomic changes allow perpetual alterations in
gene readout in cells in the CNS affecting neuronal function
and physiology. For example, a central regulator of homeostasis
in the brain, the brain-derived neurotrophic factor (BDNF), a
member of the neurotrophin family of proteins that plays crucial
Frontiers in Cellular Neuroscience
roles in the development, maintenance, and plasticity of the
CNS (Chao et al., 2006) have been demonstrated to play an
important role on different psychiatric disorders associated with
early-life adversity, including depression; schizophrenia, bipolar
disorder and autism. Even when the underlying mechanisms of
the alterations over the expression of BDNF are unknown in
these conditions, epigenetic modifications seem as a plausible
candidate, as early-life exposures, chronic emotional stimuli, or
even emotional behavior, disrupts epigenetic programming in the
brain with lasting consequences for gene expression and behavior
(Renthal et al., 2007; LaPlant et al., 2010; Kundakovic et al.,
2014).
However, epigenetics is such a new field of science that in most
of the cases, its impact has not been fully demonstrated. Even
though, it is now clear that there is a dynamic interplay between
genes and experience, a clearly delineated and biochemically
driven mechanistic interface between genes and environment, this
interface is epigenetics (Sweatt, 2013).
ALZHEIMER’S DISEASE AND EPIGENETICS
Alzheimer’s disease (AD) is an age-related and slowly
neurodegenerative disorder of the brain and the most common
form of dementia in the elderly (Sezgin and Dincer, 2014). The
disease is clinically characterized by progressive memory loss and
cognitive impairment. Moreover, the histopathological features
of AD are senile plaques composed of amyloid beta (Aβ) fibrils
and neurofibrillary tangles composed of microtubule-associated
protein tau, combined with massive cholinergic neuronal loss,
mainly in the hippocampus and association regions of neocortex
(Hardy, 2006; Ballatore et al., 2007). This disease currently affects
approximately 2% of the population in industrialized countries
and its incidence will increase dramatically over the time (Sezgin
and Dincer, 2014).
AD is a multifactorial disease involving; genetic, metabolic,
nutritional, environmental and social factors that are associated
with onset and progression of the pathology. For this reason, and
considering that the main risk factor of this disorder is aging, it is
reasonable to think that life history such hypertension, diabetes,
inflammation, obesity or head injury are closely related with
AD (Marques et al., 2011). However, how these factors induce
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Epigenetic mechanisms in neurological and neurodegenerative diseases
epigenetic changes that mediate the network genes involved in this
disease is a question that remains to be answered.
At present, studies of epigenetic changes in AD are starting to
emerge. As we mentioned before, aging is the most important risk
factor for AD an epigenetic changes have been observed in aging
tissues. Recently, it has been observed that environmental factors
even transient ones in early life can induce AD-like pathogenesis
in association with aging (Wu et al., 2008a). Furthermore, a
difference in DNA methylation patterns typical of brain region
and aging has been identified in this context (Balazs, 2014). In
this regard, a recent study by Hernandez et al. examined the
DNA methylation patterns in >27,000 CpG sites from donors
ranging in age 4 months to 102 years and a strong relationship
was found between DNA methylation and aging. Moreover, in the
temporal and frontal cortices pons and cerebellum regions, more
than 1,000 associations were found between DNA methylation
at CpG sites and age and some associations were significant in
all four regions. Interestingly, the majority of the association sites
were in CpG islands and the pattern was similar in the frontal
cortex, temporal cortex and pons, but different in cerebellum.
These results suggest that and age-dependent increase in DNA
methylation may be important for maintaining gene expression
with age (Hernandez et al., 2011).
As it has been reported in many studies, memory can be
compromised during aging. Preclinical and basic studies have
shown that epigenetic mechanisms are involved in formation
and maintenance of memory (for reviews, see Levenson and
Sweatt, 2005; Zovkic et al., 2013; Jarome et al., 2014). For
example, inhibition of DNA methylation has deleterious effects
on neuronal plasticity together with histone modifications (Day
and Sweatt, 2011; Zovkic et al., 2013). Moreover, it has been
observed that associative learning was impaired in 16-monthold mice compared with that of 3-month-old mice which was
associated with specific reduction in acetylation of H4K12 (Peleg
et al., 2010).
Until now, most of the studies have analyzed DNA
methylation in the brain of AD patients (Balazs, 2014).
In this regard, a variety of studies suggest a genome-wide
decrease in DNA methylation present in aging and AD
patients (Table 2; Mastroeni et al., 2011). Interestingly, the
folate/methionine metabolism is critically linked with DNA
methylation mechanisms, consistently with this fact; studies show
that folate and S-adenosyl methionine are significantly decreased
in AD (Bottiglieri et al., 1990; Morrison et al., 1996). All this
data indicates that AD patients produce a hypomethylation
across the DNA genome. Recently, Bakulski et al. provided a
semi-unbiased, quantitative, genome-wide localization of DNA
epigenetic differences in frontal cortex of control and AD cases.
These authors determined DNA methylation of 27, 587 CpG
sites spanning 14,475 genes. Interestingly, they found that in
control samples, the methylation state is markedly affected by
age, with about the same number of sites being hypermethylated
as hypomethylated with age. Compared with controls, 6% of
genes featured on the array were differentially methylated in
AD samples, but the mean difference was relatively modest
(2.9%). Gene ontology analysis revealed a relationship between
the main disease-specific methylation loci and several molecular
Frontiers in Cellular Neuroscience
Table 2 | Epigenetic modifications implicated in Alzheimer’s disease.
Observation
Sample
APP promoter hypomethylation in
Alzheimer’s disease patients (Miller, 2003).
Hypomethylation of promoters of ribosomal
genes with aging (Decottignies and d’Adda
di Fagagna, 2011).
Decrements in DNA methylation
(Al-Mahdawi et al., 2014).
Differences in DNA methylation in a twin
pair discordant for Alzheimer’s disease
(Al-Mahdawi et al., 2014).
APP promoter methylation
influenced by sex steroids and aging
(Maloney et al., 2012).
PSEN1 is regulated by DNA methylation in
response to metabolic stimuli
(Zetzsche et al., 2010).
Human brains.
Human lymphocytes.
Human prefrontal cortex.
Human temporal neocortex.
Intact and gonadectomized
mice brains.
Non-human primate cortical
areas of mice brains.
functions and biological processes, including hypermethylation
of genes involved in transcription and DNA replication, while
membrane transporters were hypomethylated (Bakulski et al.,
2012).
Also, some reports have focused on research DNA methylation
at the 50 promoter regions of candidate genes according to the
basis of hypothesis concerning the molecular mechanisms of
AD as microtubule-associated protein tau, amyloid precursor
protein (APP) and preseniline-1 genes in the frontal cortex
and hippocampus of both control and AD cases at different
Braak stages. Interestingly, there wasn’t any significant difference
on CpG methylation between the control and AD samples
(Barrachina and Ferrer, 2009). Other studies have reported
hypomethylation of APP in the promoter region of normal 70
year-old human brain (Tohgi et al., 1999). However, as mentioned
above, no difference was found in methylation of selected regions
of the APP gene in various stages of AD progression (Barrachina
and Ferrer, 2009). Also, it has been found that the change in
methylation status differed among transcription factor binding
sites of tau promoter (Wang et al., 2013).
Additionally to DNA methylation, histone modifications have
been studied in recent years. Francis et al. investigated histone
acetylation in mouse models of AD. In APP/presenilin1 double
mutant transgenic mice, associative learning was impaired and
this was linked to a marked reduction in H4K14 histone
acetylation (Francis et al., 2009). Furthermore, studies in vitro
have shown that exposure of cortical and hippocampal cultures
to Aβ oligomers resulted in increased levels of acetylated H3K14
and a loss of dendritic spines, which was prevented by inhibition
of histone acetyl transferase. Also, in young pre-plaque AD
transgenic mice, these authors observed markedly increased
levels of H3K14 and H3K9me2 compared with those of wildtype non-transgenic mice. Most importantly, similar changes
were observed in histone transcription activating and repressive
marks in the occipital cortex of AD samples (Lithner et al.,
2013).
Although there are now treatments against AD, these are only
palliatives and the pathology is currently incurable, whereby,
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Epigenetic mechanisms in neurological and neurodegenerative diseases
there is an intense interest in the development of new potential
therapies. Epigenetic therapies have achieved some progress in
the field of cancer, thus, several inhibitors of HDACs and DNA
methylation are approved for hematological malignances by the
US Food and Drug Administration and have been in clinical use
for several years (Wu et al., 2008a). HDAC inhibitors (HDACIs)
are the most thoroughly studied and have shown acceptable
results in AD models. The inhibitors widely used in clinical
research include trichostatin A (TSA), valproic acid (VPA),
sodium 4-phenylbutyrate (4-PBA) and vorinostat (SAHA) (Wang
et al., 2013).
In a study conducted by Su et al., VPA showed to inhibit Aβ
production in HEK293 cell transfected with a plasmid carrying
the Swedish APP751 mutation. Interestingly, using the APPV717F
transgenic model of AD, VPA was able to inhibit Aβ production
in the brain of mice at biologically relevant doses of 400 mg/kg
(Su et al., 2004). In another study, VPA showed to decrease Aβ
production and alleviate behavioral deficits by inhibiting GSK3β-mediated γ-secretase cleavage of APP in APP23 transgenic
mice (Qing et al., 2008). These results give us the idea about the
possible contribution of epigenetic modifications in AD, which
suggests that the drugs targeting epigenetic process may be of
future therapeutic value (Wang et al., 2013).
As mentioned widely in scientific literature, the interaction
between diet and epigenetics is the best documented in cancer
pathology (Ho et al., 2009; Shu et al., 2010). Furthermore,
based on evidence in support of epigenomics in regulating
gene expression in stress-mediated AD risk factors, and the
pathophysiology of AD, there has been growing interest in
examining whether diet and nutraceuticals targeting epigenomics
may prevent, delay, or reverse the course of AD (Chiu et al.,
2014). In this regard, the Mediterranean diet rich in vegetables,
fruits and nuts, legumes, olive oil and fish with relative low
intakes of red meat has been suggested to reduce the risk for AD
onset (Scarmeas et al., 2009; Frisardi et al., 2010). Other studies
appoint that anti-oxidant-rich diets and consumption of dietary
phytochemical such as caffeic acid, epigallocatechin-3-gallate,
Gingko biloba, resveratrol and phenolic compounds present in
red wine slowed down disease progression by inhibiting Aβ
production or amyloid aggregation in animal models (Kolosova
et al., 2006).
It is well known that DNA methylation occurs within
folate/methionine/homocysteine (HCY) metabolism which
uses micronutrients such as folate, methionine, choline and
betaine enzyme’s cofactors (Chouliaras et al., 2010; Wang et al.,
2013). Diverse reactions occur and methionine is converted
to S-adenosyl-methionine (SAM) and then converted to
S-adenosyl-homocysteine (SAH), which in turn is converted
to HYC in a reversible reaction. Most important, SAM is the
common methyl donor for DNA methylation that regulates
gene expression and determines the chromosome conformation
(Sezgin and Dincer, 2014). An early study showed that SAM levels
have been found to be decreased in post-mortem AD patients
(Morrison et al., 1996). Also, lower bioavailability of SAM causes
changes in the expression of genes involved in APP metabolism
because this metabolite maintains the appropriate methylation of
genes involved in APP processing (Sezgin and Dincer, 2014). Fuso
Frontiers in Cellular Neuroscience
et al. recently reported that reduction of folate and Vitamin B12
in culture medium of neuroblastoma cell lines cause a reduction
in SAM levels resulting in an increase of PSEN1 and BACE
levels together with Aβ production. Conversely, the simultaneous
administration of SAM to the deficient medium restored the
normal gene expression and reduced the Aβ levels (Fuso et al.,
2007). Interestingly, the same group demonstrated that Vitamin
B deficient-animals have shown that SAM inhibits the increase
in progression of Alzheimer-like features (Fuso et al., 2012).
This data suggests that folate or Vitamin B12-rich diets could be
beneficial as therapy for AD patients; however, more studies are
needed.
PARKINSON’S DISEASE AND EPIGENETICS
Parkinson’s disease (PD) is the second most common
neurodegenerative disorder after AD affecting approximately
1–2% of the population over the age of 65 and reaching a
prevalence of almost 4% in those aged above 85. Resting tremor,
bradykinesia, rigidity, and postural instability are the main
clinical symptoms of the disease often accompanied by nonmotor symptoms including autonomic insufficiency, cognitive
impairment, and sleep disorders (Thomas and Beal, 2011;
Coppedè, 2014). The brain of PD individuals is pathologically
characterized by a progressive loss of neuromelanin containing
dopaminergic neurons in the substantia nigra with the presence
of eosinophilic, intracytoplasmic inclusions termed as Lewy
bodies (structures containing aggregates of α-synuclein as well
as other substances) and Lewy neurites in surviving neurons.
Unfortunately, only some improvements of the symptoms
are offered by current treatments based on levodopa and
dopaminergic therapy, but there is no currently available
treatment to avoid the progression of the disease (Thomas and
Beal, 2011; Coppedè, 2014).
The vast majority of PD cases are idiopathic forms, likely
resulting from a combination of polygenic inheritance,
environmental exposures, and complex gene-environment
interactions imposed on slow and sustained neuronal dysfunction
due to aging (Migliore and Coppedè, 2009). In a minority of
the cases, PD is inherited as Mendelian trail, and studies in
PD families allowed the identification of at least 15 PD loci
(PARK1-15) and several causative genes (Nuytemans et al., 2010).
In addition, there are genes such as LRRK2, SNCA, MAPT and
GBA that are associated with sporadic PD without family history
(Table 3; Coppedè, 2012).
Most of the studies evaluating the role of epigenetic
in pathogenesis have focused on the analysis of promoter
methylation of causative PD genes in post-mortem brains and
peripheral blood; however, the role of DNA methylation and its
links to PD pathogenesis is currently unclear (Coppedè, 2012).
Recent studies have shown that methylation of SNCA gene (the
gene coding for α-synuclein) may be involved in disease via
structural changes or overexpression of the protein, leading to
protein aggregation or via impaired gene expression (Ammal
Kaidery et al., 2013). In this regard, methylation of SNCA
intron 1 has been demonstrated to be associated with decreased
SNCA transcription, whereas reduced methylation at this site
was found to be decreased in several brain regions, including
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February 2015 | Volume 9 | Article 58 | 6
Landgrave-Gómez et al.
Epigenetic mechanisms in neurological and neurodegenerative diseases
Table 3 | Epigenetic modifications of Parkinson’s disease related
genes.
Gene
Observation
SNCA
Reduced SNCA methylation in the substantia nigra of
PD patients.
SNCA gene silencing mediated by histone methylation
(Nalls et al., 2014).
Histone deacetylases inhibitors are neuroprotective
against α-synuclein mediated neurotoxicity in PD
animal models (IPDGC, 2011).
Mutant LRKK2 antagonizes miR-184 in Drosophila
melanogaster Parkinson’s disease models (IPDGC,
2011).
let-7 family miRNAs were under-expressed in parkin
transgenic C.elegans (Asikainen et al., 2010)
Aberrant gene methylation in post-mortem Parkinson’s
disease brains (IPDGC, 2011)
LRRK2
Parkin
PARK16/lq32,
GPNMB
the subtancia nigra of sporadic patients, causing the increased
expression of the SNCA gene (Jowaed et al., 2010). These results
raise the possibility that the increased α-synuclein production
that is associated with PD may result from increased SNCA
expression, as a consequence of a decreased methylation state
of its gene (Ammal Kaidery et al., 2013). Additionally, it has
been demonstrated that α-synuclein sequesters DNMT1 in the
cytoplasm, leading to global DNA hypomethylation in PD and
dementia with Lewy body in post-mortem brains, as well as in
transgenic mouse models (Desplats et al., 2011). Conversely, the
overexpression DNMT1 in both transgenic mouse models and
cellular cultures restore the nuclear level of the enzyme (Ammal
Kaidery et al., 2013).
The regulation of SNCA by epigenetic histone modifications
is yet to be studied in human PD brains. Studies in cell cultures
and animal models of the disease, such as those induced by
mitochondrial toxins, including 1-methyl-4-phenylpyridinium
(MPP+ ), paraquat, rotenone, or those overexpressing human
α-synuclein, have revealed that α-synuclein translocates into
the nucleus interacting with histones and inhibiting histone
acetylation (Goers et al., 2003). Furthermore, in Drosophila
models, nuclear-targeted α-synuclein has been shown to bind to
histones and reduce histone 3 acetylation through its association
with HDAC1 and SIRT2 (Kontopoulos et al., 2006).
In recent years, there has been considerable progress in
the development of epigenetic-based drugs for the treatment
of neurodegenerative disorders such as PD. Such inhibitors
of HDACs and DNMTs are currently approved and available
for clinical investigation (Xu et al., 2012). In this regard,
the targeted downregulation of SIRT2 has been shown to
ameliorate α-synuclein toxicity and dopaminergic loss in flies
and in primary mesencephalic culture. Moreover, toxicity
associated with nuclear-targeted α-synuclein in both SH-SY5Y
neuroblastoma cells and flies can be rescued by using HDACIs
(Outeiro et al., 2007), thus, HDACIs have been theorized to be
efficacious in neurodegenerative diseases (Harrison and Dexter,
2013). In this regard, Wu et al. demonstrated that trichostain A
(a well-known HDAC inhibitor), protects dopaminergic neurons
Frontiers in Cellular Neuroscience
from MPP+ toxicity in primary neuron-glia co-cultures in a
dose dependent manner (Wu et al., 2008b). Moreover, Kid
and Schneider demonstrated that vorinostat (another HDAC
inhibitor) protected two different dopaminergic neuronal cell
lines from apoptosis induced by MPP+ (Kidd and Schneider,
2010), thus, the above results give us an idea about the alternative
therapy by inhibiting HDACs in PD patients.
Although the etiology of PD is still unknown, multiple lines of
evidence support oxidative stress and mitochondrial dysfunction
as part of the pathogenic cascade. It would be interesting to
know whether antioxidants-rich diets that have a helpful effect
in other degenerative disease such as AD (Kolosova et al., 2006),
could have the same effect in PD patients. To this regard, therapy
focusing on nutrition, neutraceutical and antioxidants as part of a
healthy lifestyle might protect against cell death and thus delay
or halt disease progress; however, clinical and basic studies are
needed to prove such hypothesis (Bega et al., 2014).
EPILEPSY AND EPIGENETICS
Epilepsy is the third most common chronic brain disorder
affecting 50 million of people worldwide (Aroniadou-Anderjaska
et al., 2008). In this disorder, a variety of structures of the central
nervous system such as the hippocampus, the amygdala and the
piriform cortex are susceptible to trigger electrical discharges that
contribute to brain damage and to the epileptogenic mechanism
(Houser, 1990; Blümcke et al., 1999). These discharges promote
some morphological changes in the hippocampus such as, cellular
death in the CA1 and mossy fiber sprouting and dispersion of the
granule cell layer, alterations that are thought to be involved in
the formation of recurrent excitatory circuits that contributes to
seizure susceptibility (Heck et al., 2004).
In this regard, it is well known that seizures can give rise
to enduring changes that reflect alterations in gene expression
patterns, contributing in this way to the hallmarks of epilepsy
(Roopra et al., 2012). Moreover, some studies suggest that
these long-term changes mediated by seizures are mediated via
modulation of chromatin structure. One transcription factor in
particular, the repressor element 1-silencing transcription factor
(REST/NRSF) has received a lot of attention due to its association
with a great sub-set of genes associated with important processes
involved in neuronal homeostasis and because it may seem to
recruit a variety of proteins that elicit epigenetic modifications
such as histone deacetylases and histone methyltransferases
(Bruce et al., 2004; Ballas and Mandel, 2005; Ballas et al., 2005;
Johnson et al., 2006; Pozzi et al., 2013). Some reports have
shown that the induction of seizures in animal models induce
an overexpression in both REST/NRSF protein and mRNA levels
(Formisano et al., 2007; Noh et al., 2012), suggesting that seizures
may cause an unbalance in the epigenetic modifications that
control important processes of neuronal homeostasis. In contrast,
recent studies have shown that REST/NRSF is induced in the
aging human brain regulating a network of genes associated
with stress resistance (Lu et al., 2014). This evidence suggests
that REST/NRSF regulates important processes in embryonic and
adult neuronal homeostasis and that the dysregulation of this
transcription factor may impair epigenetic modifications that
regulate precisely an important network of genes contributing
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February 2015 | Volume 9 | Article 58 | 7
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Epigenetic mechanisms in neurological and neurodegenerative diseases
to distinct neurological/ neurodegenerative disorders such as
epilepsy or AD.
From a public health perspective, an alternative for the
treatment of epilepsy is a change of lifestyle or diet. These
methods have probably been used for over 2000 years and actually
metabolic regulation of neuronal excitability is increasingly
recognized as a factor in seizure pathologies and control
(Stafstrom et al., 2008; Yuen and Sander, 2014). In this way,
approximately half of the pharmacoresistant patients that have
tried metabolism based therapies experience seizure control,
opening the possibility of a strong link between the environments,
in this case nutrition, with this pathology (Greene et al., 2003;
Bough et al., 2006; Marsh et al., 2006; Patel et al., 2010).
These studies suggest that metabolism-based therapies such
as ketogenic diets, calorie restriction or intermittent fasting leads
to a range of biochemical and metabolic changes that induce a
metabolic shift in pathways such as glycolysis, ketogenesis or beta
oxidation, modifications that have been shown to increase seizure
thresholds and to decrease epileptogenesis in animal models
(Marsh et al., 2006; Patel et al., 2010).
Moreover, recent studies have shown that environmental
inputs such as nutrition or exercise modulates cell metabolism,
and critical links between metabolism and epigenetic control
are beginning to emerge (Sassone-Corsi, 2013). For example,
the availability of specific metabolites such as acetyl-coenzyme
A (acetyl-coA) and nicotinamide adenine dinucleotide (NAD+ )
dictates the efficacy of histone deacetylases (Katada et al., 2012).
In this regard, it has been shown that beta hydroxybutyrate
(β-HB), a ketone body that rises with ketogenic diets, during
strenuous exercise or during fasting (Newman and Verdin,
2014), acts as an endogenous inhibitor of histone deacetylases
linking in a precise way metabolism, epigenetics and epilepsy
(Shimazu et al., 2013). Thus, these studies strongly suggest that
the neuroprotective effects exerted by these kinds of therapies
are not only mediated via metabolism alterations but also by
epigenetic modifications that may be involved in the expression
of an unknown sub-set of genes related to epilepsy.
Other interesting epigenetic modifications involved in
epilepsy are methylation of DNA. In this field, Kobow et al.
using Methyl-seq, mapped for the first time the global DNA
methylation patterns in chronic epileptic rats; they showed that
chronic epilepsy in animal models is characterized for a global
hypermethylation on DNA. Moreover, this group shows that
ketogenic diets diminish this increase of DNA methylation,
suggesting that these kinds of therapies exert their effect not only
modulating metabolism, but also via epigenetic modifications
(Kobow et al., 2013). More importantly, it opened the possibility
for the development of new metabolism based therapies designed
to regulate these epigenetic modifications contributing to the
inhibition of the seizure threshold in epilepsy.
THE ROLE OF REST/NRSF IN NEUROLOGICAL DISORDERS
A growing body of literature suggests that long-term changes
in gene transcription associated with a lot of neurological
disorders are mediated via modulation of chromatin structure.
One transcription factor in particular, REST/NRSF (repressor
element 1-silencing transcription factor) (Figure 4), has received
Frontiers in Cellular Neuroscience
FIGURE 4 | REST structure and their interactions with other proteins.
REST modulates the expression of its target genes by recruiting a host of
lysine-modifying enzymes. Numbers refer to amino acid residues. Colored
molecules possess enzymatic activity.
a lot of attention due to the possibility that it may control
the expression of approximately 1,300 genes (Bruce et al., 2004;
Johnson et al., 2006) that could be associated with a variety
of processes that are important for neuronal homeostasis such
as; synaptic transmission, synaptogenesis, excitability or even
neurogenesis (Ballas and Mandel, 2005; D’Alessandro et al.,
2009). REST modulates these genes in the nervous system
recruiting protein complexes that elicit different epigenetic
modifications (Figure 4; Roopra et al., 2012). Now it has been
shown that REST is upregulated in pyramidal and dentate gyrus
neurons after status epilepticus induced by kainate (Palm et al.,
1998) or even by ischaemic insults (Formisano et al., 2007;
Noh et al., 2012). Therefore, the upregulation of REST has
been previously considered as harmful in mature neurons. In
contrast, recent studies have shown that induced expression
of REST/NRSF in mature hippocampal neurons is a protective
mechanism that modulates the inhibitory homeostatic control of
intrinsic excitability (Pozzi et al., 2013). Moreover, it has been
shown that REST/NRSF protects neurons from age-related toxic
insults in AD and surprisingly these levels seems to be associated
with preservation of cognitive function and increased longevity
(Lu et al., 2014). These findings suggest that basal levels of
REST/NRSF are necessary for a normal physiological condition
in the adult brain and that elevated levels of REST/NRSF,
characteristic of epilepsy, may not be an epileptogenic factor,
rather it seems to be a homeostatic mechanism triggered by
repeated hyper-excitability stimuli. This is an open issue that
needs further investigation.
CONCLUDING REMARKS
As we state in this manuscript, one of the main factors
that contributes to a variety of the most common diseases
is the environment. Many epigenetic enzymes are potentially
susceptible to changes in the levels of a variety of metabolites,
and are, hence, poised to respond to changes on environment. In
this sense, it has been demonstrated that changing our lifestyle
could mediate great beneficial effects regulating a network of
genes via the modulation of chromatin structure, providing new
alternatives for the prevention of many diseases.
Different questions remain to be answered including which
epigenetic modifications are implicated in neurological disorders,
how does the environment mediate these changes, could
pharmacological inhibitors of these modifications provide an
alternative for treating disease, and so on. Increasing evidence
on this field had taught us that these modifications are capable
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February 2015 | Volume 9 | Article 58 | 8
Landgrave-Gómez et al.
Epigenetic mechanisms in neurological and neurodegenerative diseases
of regulating great networks of genes that can influence a variety
of physiological processes important for overall homeostasis and
that the disruption of this balance can increase the risk of disease.
From a public health perspective, we need to better understand
which alterations in metabolism and in chromatin structure
cause disease and, maybe, it will be possible to design rationale
metabolism-based therapies that could function as alternative
treatments of these kinds of disorders.
ACKNOWLEDGMENTS
This work was supported by grants from Programa de
Apoyo a Proyectos de Investigación e Innovación Tecnológica,
DGAPA-PAPIIT (IN211913) and Consejo Nacional de Ciencia y
Tecnología, CONACyT (239594). The authors want to thank Mrs.
Josefina Bolado for editing this English-language text chapter.
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Conflict of Interest Statement: The authors declare that the research was conducted
in the absence of any commercial or financial relationships that could be construed
as a potential conflict of interest.
Received: 17 October 2014; accepted: 06 February 2015; published online: 27 February
2015.
Citation: Landgrave-Gómez J, Mercado-Gómez O and Guevara-Guzmán R (2015)
Epigenetic mechanisms in neurological and neurodegenerative diseases. Front. Cell.
Neurosci. 9:58. doi: 10.3389/fncel.2015.00058
This article was submitted to the journal Frontiers in Cellular Neuroscience.
Copyright © 2015 Landgrave-Gómez, Mercado-Gómez and Guevara-Guzmán. This
is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution and reproduction in other forums is
permitted, provided the original author(s) or licensor are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice. No
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