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Epigenetics and the nervous system.

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NEUROLOGICAL PROGRESS
Epigenetics and the Nervous System
Mark F. Mehler, MD
We are in the midst of a revolution in the genomic sciences that will forever change the way we view biology and medicine,
particularly with respect to brain form, function, development, evolution, plasticity, neurological disease pathogenesis and neural
regenerative potential. The application of epigenetic principles has already begun to identify and characterize previously unrecognized molecular signatures of disease latency, onset and progression, mechanisms underlying disease pathogenesis, and responses to new and evolving therapeutic modalities. Moreover, epigenomic medicine promises to usher in a new era of neurological therapeutics designed to promote disease prevention and recovery of seemingly lost neurological function via
reprogramming of stem cells, redirecting cell fate decisions and dynamically modulating neural network plasticity and connectivity.
Ann Neurol 2008;64:602– 617
First, the four general categories of epigenetic processes
(DNA methylation, chromatin remodeling, non-coding
RNAs (ncRNAs), and RNA and DNA editing) are introduced, and their roles in mediating fundamental
nervous system attributes, such as stem cell specification and learning and memory, are described. The epigenetic mechanisms that contribute to the pathogenesis
of various neurological diseases are then introduced,
followed by a discussion of environmental epigenomics
and the new classes of neurologic therapeutics based on
targeting epigenetic processes.
Molecular Underpinnings of a New Science of
Brain and Behavior
Epigenetics is the study of the molecular and cellular
mechanisms governing the function of single genes and
large gene networks, from dynamic expression profiles
to complex modulation and functional integration, as
well as the evolving molecular interface mediating
gene-environmental interactions.1 By providing an integrated view, epigenetics is the first biomedical discipline capable of explaining the biological complexity of
life, and uncovering the mysteries governing higherorder cognitive and behavioral repertoires. Nervous system development, plasticity, homeostasis, and evolutionary innovations in form and function are
orchestrated by four major classes of epigenetic processes: DNA methylation, chromatin remodeling, non-
From the Departments of Neurology, Neuroscience, and Psychiatry
and Behavioral Sciences, Institute for Brain Disorders and Neural
Regeneration, The Rose F. Kennedy Center for Research on Intellectual and Developmental Disabilities and the Einstein Cancer
Center, Albert Einstein College of Medicine, Bronx, NY.
Additional Supporting Information may be found in the online version of this article.
Received Jun 27, 2008, and in revised form Oct 31. Accepted for
publication Nov 24, 2008.
602
coding RNAs (ncRNAs), and RNA and DNA editing
(Fig 1).2– 6
DNA Methylation
DNA methylation preferentially represses local and
genome-wide gene transcription catalyzed by DNA
methyltransferases (DNMTs) acting at cytosine
dinucleotides (CpG).5 Non-protein coding regions of
individual genes (intronic), and between genes (intergenic) are methylated to preserve genomic integrity and
to establish and maintain cell identity. This is achieved
by stabilizing DNA associated with chromosome segregation during mitosis (centromeres), aging (telomeres),
mobile parasitic repeat sequences (DNA transposons,
retrotransposons), and by modulating gene dosage
from maternal and paternal alleles (genomic imprinting, X-chromosome inactivation).7
DNA methylation occurs within the context of nucleosome and chromatin remodeling, ncRNAs and RNA
editing (see below), providing a mechanism for reversible
as well as short- and long-term gene silencing and heritability.8,9 DNA methylation is associated with histone
modifications through methyl CpG binding proteins
(MBDs) in concert with dynamic complexes containing
histone-modifying enzymes that promote gene repression and DNA replication and repair.5 DNA methylation establishes appropriate neuronal identity by preventing premature neural stem cell maturation and
Potential conflict of interest: Nothing to report
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21595
Address correspondence to Dr Mehler, Institute for Brain Disorders
and Neural Regeneration, Albert Einstein College of Medicine, Rose
F. Kennedy Center 401, 1410 Pelham Parkway South, Bronx, NY
10461. E-mail: mehler@aecom.yu.edu
© 2008 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
metabolic/homeostatic/environmental cues
genome regulation
essential cellular functions
• genomic imprinting
• gene dosage effects
• long-range gene modulation
• genomic stability
• epigenetic reprogramming:
-DNA/RNA/protein
• multigenerational heritability
• cell cycle regulation
• DNA replication/repair/recombination
• nuclear reorganization
• telomere maintenance
• gene transcription
• post-transcriptional processing
DNA methylation
histone
modifications
RNA/DNA
editing
nucleosome
repositioning
chromatin
remodeling
non-coding RNAs
neural development
adult brain functions
• neural induction
• regional neural patterning
• stem cell self-renewal/maturation
• neuronal/glial subtype specification
• terminal differentiation
• synaptogenesis
• neuronal homeostasis/plasticity
• neural network connectivity
• trans-neuronal signaling
• adult neurogenesis
• neural regeneration
• memory formation
• higher-order cognitive processing
Fig 1. Schematic representation of the major classes of epigenetic mechanisms, functional interrelationships between these processes,
dynamic regulation by cell-intrinsic as well as environmental cues and influences on genome regulation, seminal cellular functions
and developing and adult nervous system homeostasis and plasticity.
alternate lineage programs.10,11 DNMTs are expressed
throughout neural development, and in the adult brain
in selective regional and cell-specific patterns including
mature stem cell generative zones mediating ongoing
neurogenesis.6 Moreover, DNMTs are actively regulated
by physiological and pathological states and interactions,
and they promote neuronal survival, plasticity and stress
responses.5,12 MBDs also have essential roles in brain
development and mature CNS functions.6,13
Histone Modifications, and Nucleosome and
Higher-Order Chromatin Remodeling
Genome-wide chromatin remodeling is required to orchestrate changing profiles of expression of individual
genes and gene networks within individual nerve cells
and neural networks in response to complex metabolic
cues, cellular processes, and environmental signals.6,14 –18
Chromatin contains units of DNA and histone, and
non-histone proteins that promote dynamic three-
Mehler: Epigenetics and the Nervous System
603
dimensional folding of DNA, and genome-wide and nuclear reorganization.16 The nucleosome consists of 147
base pairs of DNA wrapped around a core of pairs of
primary (H2A, H2B, H3, H4), linker (H1) and specialized variant histones.15,19 Nucleosomes exist to promote
the orderly progression of local gene transcription and
DNA repair, and they contain molecular recruitment
platforms for genome-wide, higher-order chromatin remodeling.17,20
A continuum of chromatin states exists, from condensed and inactive (“heterochromatin”), to open and
active (“euchromatin”) forms. Some genomic regions
encompass highly repressed long-term inactive states to
promote genomic stability; some represent an inactive
but permissive state to facilitate cellular processes, including cell division; some exist in a “poised” state associated with “transcriptional memory” to promote
neural developmental processes.16,20 –24 Heterochromatin exists as “constitutive” forms to promote genomic
stability, long-range gene interactions, recruitment of
ncRNAs, and gene dosage effects. “Facultative” forms
of heterochromatin exist to mediate developmental
processes.16,18,21,22,25 Boundary elements between adjacent heterochromatic and euchromatic regions exist
to preserve the integrity of gene expression, and to promote interactions between distant genes through DNA
looping.20 –23,26,27
Primary histone modifications represent a sophisticated molecular code to modulate many cellular processes including transcription, translation, and DNA
replication and repair.15–18 Numerous post-translational
modifications of individual histone proteins occur at
specific amino acid residues (lysine [K], arginine [R],
serine [S], threonine [T], glutamate [E]) by the actions
of enzymes with complex activity profiles in response to
cellular and environmental cues.4,8,16,17,28 Histonemodifying enzymes also target non-histone cellular proteins. Histone-modifying enzymes are components of
transcriptional supercomplexes involved in coordinating
local and long-distant chromosomal and nuclear reorganization, and evolving gene and neural network programs.4,17,26,29,30
Chromatin “codes” promote diverse epigenetic processes including genomic imprinting, X-chromosome
inactivation, heterochromatin formation, gene silencing, and heritable epigenetic reprogramming.22,31–35
Higher-order chromatin codes are orchestrated by
polycomb (PcG) and trithorax (TrxG) group protein
complexes. These complexes bind to regulatory domains of diverse gene targets through PcG- (“PRE”)
and TrxG- (“TRE”) response elements to establish signaling platforms for enzymes involved in DNA methylation, histone modifications, nucleosome remodeling,
and RNA processing.27 PcG- and TrxG-mediated
chromosome condensation and relaxation, respectively,
promote DNA replication and repair, mitosis, recom-
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bination, transcription, and apoptosis. 17,20,21,27,28,33
Nucleosome-remodeling enzymes mediate nucleosome
repositioning to regulate the directionality and progression of gene transcription, and to prevent transcription
initiation from cryptic sites and “read-through” to
neighboring genes.28,36 Histone modifications and
chromatin remodeling direct neural stem cell maintenance and fate restriction, neuronal and glial subtype
specification, differentiation, homeostasis, neural network plasticity, learning and memory, and brain aging;
these processes are deregulated in neuropsychiatric diseases.3,4,6,14,16,29,37– 40
Non-Coding RNAs
The fraction of non-protein coding genes has greatly
increased as a function of evolutionary complexity,
whereas the absolute number of protein-coding genes
has remained essentially unchanged.41– 43 ncRNAs are
actively transcribed in complex and multi-layered patterns from both DNA strands.44,45 These transcripts
can be further processed to give rise to small and
longer regulatory ncRNAs that function through
“sequence-specific” recognition of DNA, RNA and
higher-order DNA: RNA complexes and through “conformational” interactions with RNA binding proteins
(RBPs), and other protein signaling networks.46,47
ncRNAs promote developmental and adult homeostatic
and plasticity processes, and gene-environmental interactions through mediating numerous epigenetic processes
including RNA post-transcriptional events.2,48 Chromatin remodeling enzymes can bind to RNA and to multifunctional RNA complexes through specialized binding
domains within chromatin remodeling enzymes and associated proteins; however, they possess little known affinity for DNA sequences.16,17,39,49 ncRNAs can influence gene expression by targeting common regulatory
proteins to DNA regulatory elements, including PREs
and TREs, which are themselves transcribed as
ncRNAs.50 –52 These ncRNAs are preferentially expressed within the mammalian nervous system.2
MicroRNAs (miRNAs) are regulatory ncRNAs that
either inhibit stability or repress translation of target
RNAs. Numerous mammalian brain-specific miRNAs
have been described with specialized roles in neural development, and adult homeostasis and plasticity.2,53,54
Distinct miRNA expression profiles exist in neuronal
subtypes, preferentially in neocortex and cerebellum.2,54 Genes encoding synaptic proteins represent
the largest subclass of miRNA targets, suggesting important roles for miRNAs in activity-dependent synaptic plasticity and memory formation; deregulation of
miRNAs result in diverse neuropsychiatric disorders.2,55 A single miRNA may differentially repress or
even activate as many as 1,000 target genes in concert
with RBPs at either the 3⬘ untranslated regions (UTRs)
or at additional regulatory sites.56 miRNAs also rapidly
and reversibly modulate gene expression and gene networks in response to complex environmental cues.54,57
RNA editing (see below) affects every step in the biogenesis, processing, and stabilizing of mature miRNAs.
RNA editing also alters the profiles of miRNA targets.54,58,59 Many miRNAs are primate- and even
human-specific, and they are undergoing rapid evolutionary selection.2 Intracellular signaling molecules mediating diverse neurodevelopmental events can directly
regulate miRNA biogenesis.60 Therefore, miRNAs play
seminal roles in neural development, adult neural plasticity, and in the pathogenesis of neuropsychiatric disorders. Additional ncRNA subclasses have been identified with preferential and diverse nervous system
functions.
Small nucleolar RNAs (snoRNAs) promote developmental and adult functional complexity through actions on chromosome dynamics, genomic imprinting,
RNA splicing, transcription, translation, cell cycle progression, and DNA repair.61– 63 Numerous brainspecific snoRNAs have been identified and each displays a unique expression profile in areas associated
with learning and memory.63 SnoRNAs, miRNAs, and
longer ncRNAs participate in genomic imprinting.
These regulatory processes enhance brain development
and mature neural functions through complex epigenetic mechanisms.2
Small Cajal body-specific RNAs (scaRNAs) promote
modifications of “spliceosomal” RNAs associated with
alternate splicing of gene transcripts to create novel
protein isoforms.64,65 Additional classes of ncRNAs,
including telomeric RNA, signal recognition particle
RNA, and piwi protein-interacting RNAs (piRNAs),
are involved in regulation of genomic architecture,
maintenance of germline integrity, senescence, and
other important cellular events.2,37,48,66 – 68 Diverse
ncRNAs interact with RBPs to regulate transcriptional
programs in response to complex environmental
cues.69 Although transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) mediate cellular housekeeping
functions, they also participate in developmental and
adult nervous system functions as indicated by targeted
mutations of tRNAs and rRNAs, which cause numerous neuropsychiatric diseases including the mitochondrial encephalomyopathies.2,70
Many longer ncRNAs are also transcribed from the
mammalian genome.44,71 Longer ncRNAs are developmentally modulated, environmentally responsive, frequently alternately spliced, rapidly evolving within the
primate and the human lineages, and they show great
abundance in brain.42,44,72,73 Longer ncRNAs participate in antisense transcription, genomic imprinting,
X-chromosome inactivation, and they are host sites for
miRNAs and snoRNAs.2,74 Different classes of longer
ncRNAs are important for neural development, bidirectional axodendritic RNA transport, and local pro-
tein synthesis required for synaptic and neural network
plasticity.2 In concert with RBPs, longer ncRNAs, including the fragile X mental retardation protein
(FMRP), promote long-term plasticity (LTP) underlying memory consolidation.2,75,76 RNA-mediated processes are also important for regulating “prion-like”
switching associated with synaptic plasticity; deregulation of these plasticity programs may predispose to
neurodegenerative diseases including the spongiform
encephalopathies.2,77–79
Many mammalian protein-coding genes have associated (“cis-acting”) antisense transcripts that modulate
their expression and function; they are also preferentially active in the nervous system where they mediate
numerous neural developmental processes, mature neuronal homeostasis, neural plasticity, and stress responses.2,80,81 Deregulation of cis-acting antisense transcripts
result in diverse neuropsychiatric diseases.2 Long distance (“trans-acting”) antisense RNAs, which are produced during evolution by gene duplication coupled to
DNA inversion, have also been implicated in multiple
neurological processes and disease states.2,82 Human
accelerated regions (HARs) display both a high degree
of mammalian conservation and accelerated evolution,
since divergence from chimpanzees. HARs have recently been defined outside of protein-coding regions
with many located adjacent to seminal neurodevelopmental genes.83 Deregulation of HAR-mediated
protein-coding gene loci, including the reelin locus,
through multiple epigenetic processes is associated with
important neuropsychiatric diseases including schizophrenia.84
RNA Editing and DNA Recoding
By promoting dynamic and reversible base recoding,
RNA editing can modulate the expression profiles and
functions of protein-coding genes and ncRNAs.85– 87
During mammalian evolution, particularly within the
hominid lineage, RNA editing has increased dramatically with brain tissue, displaying the highest levels and
most complex forms of adenosine to inosine (A-I)
RNA editing mediated by adenosine deaminases acting
on RNAs (ADARs).86,88 In mammals, there are three
ADAR enzymes: ADAR1 and ADAR2, which are preferentially expressed, and ADAR3, which is restricted to
the nervous system.86,89
RNA editing enzymes exhibit complex and dynamic
expression and subcellular localization during brain development. ADARs undergo complex regulation by behavioral state, environmental cues, genetic background,
cell signaling, and feedback regulation.2,90 ADARs orchestrate intricate patterns of site-specific editing of individual RNAs with complex functional consequences.2,90 Adenosine deaminases acting on tRNAs
(ADAT1-3) modify codon recognition in the process
of mRNA decoding; they greatly expand protein diver-
Mehler: Epigenetics and the Nervous System
605
sity within the developing and adult brain.88 RNA editing selectively edits and regulates the biophysical
properties of protein-coding genes to fine-tune neural
transmission and presynaptic vesicle release within activated neural networks.85,86,88 RNA editing can significantly modify miRNA biogenesis, and target genes
and other ncRNAs.2,47,54,58,90
Edited gene products participate in a spectrum of
neurodevelopmental and adult regulatory functions including neuronal homeostasis, neural network plasticity, and epigenetic modulation of learning and memory.90 RNA editing can also alter the choice and
location of splicing sites, snoRNA precursors, antisense
RNAs, RBPs, genomic imprinting, X-chromosome inactivation, and chromatin architecture.2,90 RNA editing mediates the intricate cognitive and behavioral output of the developing and mature nervous system;
deregulation of ADARs, including hypo- or hyperediting, is associated with a spectrum of neurodevelopmental, neurodegenerative, neurooncological, and neuropsychiatric diseases.2,88,91–93
Cytidine deaminases, termed the “apolipoprotein B
editing catalytic subunit” (APOBEC) family, participate in recoding of both RNA and DNA by changing
cytidine and deoxycytidine to uridine and deoxyuridine, respectively.94 Four mouse enzymes (APOBEC-1,
-2, CEM15 and activation-induced cytidine deaminase
[AID]) exist, whereas the CEM15/APOBEC-3 family
has expanded in humans to seven members including
APOBEC-3G, which is preferentially expressed in
post-mitotic neurons and is under positive evolutionary
selection.90,94 –96
APOBEC enzymes have a spectrum of DNA and
RNA targets, and they are regulated by subcellular localization, nucleocytoplasmic transport, alternate splicing, post-translational modifications, interactions with
RNA regulatory factors, RBPs, cellular metabolites,
and environmental cues. APOBEC enzymes modify
synaptic functions by modulating the degradation of
miRNA-targeted mRNAs in synapse-associated organelles (“processing bodies”, “stress granules”) and by
preventing the inhibition of local protein synthesis by
miRNAs.90,94 APOBEC editing restricts the migration
of transposable genomic repetitive elements to enhance
genomic stability. APOBEC editing also enhances antiretroviral activity, recombination, somatic hypermutation, and gene conversion to promote molecular diversity, plasticity and host defenses.2,90,94,97,98 Deregulation
of APOBEC enzymes are associated with several neurological diseases exhibiting prominent cognitive dysfunction.90
The New Genomic Landscape and the Advent
of RNA Regulatory Circuitry
The new genomic landscape consists of sophisticated
regulatory domains and epigenetic modifiers located well
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beyond traditional 5⬘ promoter/enhancer regions of
genes to promote fine-level modulation of gene expression and functional gene networks (Fig 2).30,44,71,99 The
majority of the genome is comprised of intricate regulatory elements that give rise to diverse classes of
ncRNAs.71 ncRNAs frequently exhibit alternate splicing
with extensive overlap of transcriptional units including
those antisense to both protein-coding as well as ncRNA
transcripts, bidirectional in association with proteincoding transcripts with common regulatory elements
and transcripts contained within the body of other genes
and exhibiting linked expression and regulation.44,71,100
Human gene organization therefore allows maintenance
of gene identity while promoting high degrees of plasticity and molecular diversity.44,101
Extensive long-range linked transcriptional regulation is mediated by complex enhancers, locus control
regions (LCRs), repressors/silencers, imprinting control
centers (ICCs) and insulators.30,99,102,103 This genomic
architecture permits novel modulation of gene function: splicing between different RNA species (“transsplicing”), and joining of multiple exons from separate
protein-coding and non-coding genes (“gene fusion”).30,99,102,104 Long-distance transcriptional activity
modulates the dynamic resetting and remodeling of the
chromatin code.20,102,105 This complex genomic architecture offers a rich substrate for the generation of different classes of longer ncRNAs, serves as precursors for
short ncRNAs, and acts in concert with other intronic
RNAs co-regulated with their parent genes.45,71 Such
diverse ncRNAs promote global (“trans-acting” RNAs)
and localized (“cis-acting” RNAs) RNA signals in concert with higher-order DNA-RNA, RNA-RNA and
both DNA- and RNA-based protein interactions to enhance complex genome-wide gene expression and function.30,47,99,106,107
Modifications in chromatin structure play important
roles in chromosome repositioning to enhance intermingling of chromosome territories through decondensation and “looping out” of DNA regions to promote
inter-chromosomal interactions, including clustering of
common gene regulatory motifs and factors.30,99,102,103
Diverse forms of inter-chromosomal interactions are
orchestrated by DNA methylation, chromatin remodeling, ncRNAs and RNA editing.30,108 Higher-order
chromosomal interactions are further regulated by transposable repetitive elements representing almost half of
the DNA sequences of the human genome.109 –111 A
small subset (Alu, LINE-1, SVA including human endogenous retrovirus K [HERV-K]) of these repetitive elements remain mobile and thus active in the human genome. These and more ancient repetitive elements
contribute to genetic diversity and functional innovations, and also cause neuropsychiatric diseases when deregulated by duplication, migration, and integration into
specific genetic loci, or by facilitating chromosome rear-
scaRNAs
dsRNAs
piRNAs
endo-siRNAs
ENOR
HAR
short ncRNAs
longer ncRNAs
(transvection)
longer ncRNAs (imprinting)
LCRs
ICCs
snoRNA
insulators
repressors/silencers
miRNA
longer ncRNA precursor
miRNA
protein-coding RNAs
“intronic”
“bidirectional”
∆RBP targeting
∆miRNA targeting
5’
3’
cis-addition
promoter
cis-disruption
+
enhancers
∆A(N)
silencing
LINE-1 SINE
exonization
alternate-splicing
3’
5’
“cis-antisense” RNA
antisense transcript
longer ncRNA (imprinting control)
Fig 2. Schematic representation of selected epigenetic regulatory processes underlying the new genome architecture (illustrated in red)
as contrasted with previous views of the organization of the classical genome (illustrated in black). Repeating small vertical red lines
represent parasitic repetitive elements under epigenetic modulation with diverse roles in regulating genomic organization and function. A(N) ⫽ polyadenylation; endo-siRNAs ⫽ endogenous-small interfering RNAs; ENOR ⫽ long expressed non-coding regions;
HAR ⫽ human accelerated regions; ICCs ⫽ imprinting control centers; LCRs ⫽ locus control regions; LINE-1 ⫽ long interspersed
nuclear elements; miRNA ⫽ microRNA; piRNAs ⫽ piwi protein-interacting RNAs; RBP ⫽ RNA binding proteins; scaRNAs ⫽
small Cajal body-specific RNAs; SINE ⫽ short interspersed nuclear elements; snoRNA ⫽ small nucleolar RNA.
rangements.109 –114 Dynamic interactions occur between
active transposable elements, including “autonomous”
(LINE-1) and “non-autonomous” (Alu, SVA) mobilization through LINE-1-encoded proteins that activate
more ancient silenced repetitive elements.114 By interacting with all classes of epigenetic regulators, transposable
elements contribute to centromeres, telomeres, insulators, promoters, enhancers, intron-exon boundaries,
genomic imprinting and X-chromosome inactivation,
transcription, alternate splicing, polyadenylation, RNA
editing, translation, epialleles (heritable but reversible
epigenetic changes in allelic gene expression), allelic interactions resulting in heritable changes to one allele
(“paramutation”), as well as extensive exaption (evolutionary or acquired gain of regulatory functions).109 –115
Stem cell-associated neural fate decisions are orchestrated
by LINE-1-mediated retrotransposon-linked events due
to insertional preference for neural developmental
genes.114
Adaptation of RNA regulatory circuits for promoting evolutionary innovations in human brain form and
function may have occurred because of unique RNA
functional properties (Fig 3).46,48,116 –119 RNA links
sequence-specific (“digital”) and conformational (“analogue”) information within the same molecule, lowers
the energy costs of information transfer, promotes accelerated evolution, serves as biosensors of environmen-
tal and homeostatic cues, and enhances adaptations to
changing environmental conditions.47
RNAs participate in extensive activity-dependent
modulation of gene and gene network expression and
function through dynamic regulation of RNA species
during axodendritic transport in association with RBPs
contained within neuronal granules and at synaptic terminals.46,47,55,75,120,121 These “RNA operons” consist
of RBPs, RNA mediators, ncRNAs, and RNA biogenesis and regulatory pathway components and metabolites that interact with 3⬘ UTRs of mRNAs to modulate gene networks.46,56
Different RNA operons promote the elaboration of
higher-order “RNA regulons” to establish unique “epigenetic memory states” at different levels of the neuraxis.46,90 Additional “embedded” information, maintained through DNA and RNA stereoisomers, introns
and intergenic regions and codon degeneracy, can furnish additional levels of epigenetic regulatory information to further enhance higher-order brain and cognitive processing.2,44,46,47,90,91,107,122 Moreover, ncRNAs
participate in diverse regulatory processes including
chromatin dynamics, transcription, post-transcriptional
processing, translation, and trans-neuronal and intercellular RNA transport and signaling.48,123
RNA trafficking has been detected between adjacent
cells, to more distal cells within the same tissue/organ
Mehler: Epigenetics and the Nervous System
607
RNA
bioenergetic
costs
UNIVERSAL
“BIOSENSOR”
DNA interactions [“digital code”]
∆shape
protein interactions [“analogue code”]
decode embedded genetic information
site-specific targeting
∆ chromosome function
∆ chromatin architecture
DNA recoding
∆ gene transcription
Reverse transcriptases
∆ axodendritic transport
DNA recombination
growth cone
∆ post-transcriptional regulation
remodeling
∆ local translation
synaptic
∆ post-translational processing
RNA editing
trans-neuronal trafficking
∆epigenetic memory states
systemic trafficking
germ-line transfer
developmental plasticity
multigenerational heritability
accelerated evolution
neural network plasticity
Fig 3. Schematic representation of the unique functional properties and seminal regulatory roles of RNA molecules and their importance in orchestrating evolutionary innovations in brain form and function through the mediation of RNA regulatory circuitry.
system, within the systemic circulation, and even
through specific pathways for transmission of systemic
RNAs back to the germline to participate in novel
forms of accelerated evolution and multigenerational
inheritance of complex cognitive and behavioral
traits.90,123,124 Activity-dependent trans-neuronal RNA
signaling thus has major implications for our understanding of molecular mechanisms underlying synaptic
and neural network plasticity and cognitive adaptations
during human brain evolution, through environmental
epigenetics, in the etiology of neuropsychiatric diseases
and for epigenetic reprogramming and development of
novel pharmacoepigenomic strategies.
Epigenetics and Neural Stem Cell Biology
The epigenetic regulation of stem cell maintenance and
fate decisions involves the transition from global transcriptional hyperactivity to massive gene silencing mediated by chromatin remodeling factors.125 By contrast, epigenetic modulation of stem cell fate restriction
and neural specification is mediated by targeted heterogeneity of gene expression via a series of slowly fluctuating global transcriptional states required to produce
unique cell identities.126 The epigenetic factor Bmi1
promotes neural stem cell maintenance by enhancing
self-renewal and by preventing cell cycle progression
from creating a susceptible window during late G1 for
alternate fate decisions: differentiation, telomere attrition, senescence, apoptosis and cell transformation (Fig
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4).40,127 Within stem cell niches, Bmi1 collaborates
with pluripotency genes to restrict the expression of
neural differentiation genes using a “bivalent” chromatin signature at targeted promoters consisting of dual
activator and repressor histone modifications.40,127,128
Neural stem cell self-renewal is also orchestrated by additional epigenetic modifiers including histonemodifying enzymes, miRNAs and RBPs.38,40,127,129
Neural stem cell lineage restriction, neuronal and
glial specification, maturation, and synaptogenesis are
also regulated by the neuron-restrictive silencing factor,
NRSF/REST, a scaffold for assembling environmentally responsive epigenetic complexes (Fig 4).29,130 –132
REST enhances context-dependent gene repression,
gene activation and long-term gene silencing by binding to diverse RE-1 consequence sequences at multiple
upstream, downstream and intragenic (intronic)
genomic regulatory sites in association with proteincoding genes and ncRNAs.29,130 In non-neuronal cells,
double-stranded neuron-restrictive silencing element
(dsNRSE) RNA converts REST from a transcriptional
repressor to a transcriptional activator during neuronal
subtype specification and differentiation.133 Multiple
miRNA species further collaborate with REST to finetune neuronal subtype specification, maturation and
neural network integration.134,135 REST recruits
DNMTs, MBDs, histone and chromatin remodeling
enzymes, transcription factors, cell cycle regulators, coregulators (CoREST), and ubiquitin proteasome degra-
Oct4
Sox2
Nanog
MPP
Bmi1
HDACs
miRs
RBPs
IP
cell cycle
arrest
MAPK P16INK4a
N/OP
GP
–
AP
OP
AP
N
OL
AS’
OL
AS’’
differentiation
CBP/HAT
TrxG
G genes
H3K27me3
+
OP
senescence
N genes
–
PcG
NP
“NSC state”
Oct4 / Sox2 / Nanog
+
NSC
REST
HDAC
1/2
LSD1
G9a
CoREST
REST
HDAC
1/2
BRG1
dsNSRE
RNA
miR-124a
MOL
∆ H3/4Ac/Me
Non-N genes
REST 4
dsNSRE
S
cell cycle arrest
senescence
apoptosis
G1
CoREST
MeCP2
REST
differentiation
G2
∆ HDAC/HAT
∆ PcG/TrxG
∆ PTB/nPTB
∆ PARP
+
N genes
+
G genes
oncogenesis
aging
+
M
INK4a
P16
senescence
apoptosis
oncogenesis
G0
Fig 4. Schematic representation of an illustrative subset of epigenetic mechanisms regulating neural stem cell biology in health and
disease throughout the lifecycle. The schematic on the upper left side represents a typical neural stem cell fate map. The schematic on
the lower left side represents progressive stages of the cell cycle and distinct normal and pathological functional outcomes following
differential epigenetic modulation of the G1-S phase of the cell cycle in stem cell progeny at the neural precursor cell stage as indicated by the dashed boxes. The schematic on the right side represents epigenetic regulatory mechanisms mediating early stem cell fate
decisions (upper right side above the first black arrow), progressive neural differentiation and effects of brain aging (lower right side
below the branching black arrows) and the seminal influences of the REST/CoREST neuronal epigenetic silencing complex in mediating all phases of neural stem cell maturation. AP ⫽ astrocyte precursors; AS’ ⫽ type I astrocytes; AS” ⫽ type II astrocytes;
BRG1 ⫽ brahma-related gene 1; Go ⫽ cell cycle quiescence; G1/S/G2/M ⫽ progressive stages of the cell cycle; G genes ⫽ glial
genes; GP ⫽ glial progenitors; HAT ⫽ histone acetyltransferase; HDAC ⫽ histone deacetylase; IP ⫽ intermediate progenitors;
LSD1 ⫽ Lysine Specific Demethylase 1; MAPK ⫽ mitogen activated protein kinase; MOL ⫽ myelinating oligodendrocytes;
MPP ⫽ multipotent progenitors; N ⫽ mature post-mitotic neurons; N genes ⫽ neuronal genes; N/OP ⫽ neuronal/oligodendrocyte
progenitors; NP ⫽ neuronal precursors; nPTB ⫽ neuronal PTB; NSC ⫽ neural stem cells; OL ⫽ mature post-mitotic oligodendrocytes; OP ⫽ oligodendrocyte precursors; PARP ⫽ polyADP ribose polymerases; PTB ⫽ polypyrimidine tract binding protein.
dation co-factors to orchestrate dynamic changes of
RE1 site occupancy, REST expression profiles and the
modification of DNA, histones, nucleosomes, higherorder chromatin codes and linked cellular processes.29,130,136 These epigenetic processes permit REST to
regulate gene expression across functional gene networks to differentially enhance stem cell self-renewal
and pluripotency, neural cell identity, maturation, connectivity and activity-dependent plasticity.29,130,131
Neural lineage specification involves epigenetic
mechanisms including DNA methylation, histone
modification, chromatin remodeling, ncRNAs and
RNA editing (Fig 4).6,38,40,129,137–140 Neurogenic and
gliogenic factors promote neural lineage specification
and maturation by global reorganization of gene promoters through dynamic modulation of DNMTs,
MBDs, and histone and chromatin remodeling enzymes.6,137,138,140 Nuclear co-repressors stabilize the
neural stem cell state by repression of direct targets of
neuronal differentiation factors to prevent recruitment
of histone-modifying factors that activate neurogenic
gene expression.138,141 Neurogenic differentiation programs, in turn, derepress neurogenic genes by removing repressive histone marks added by PcG proteins
and histone-modifying enzymes utilizing alternate
histone-modifying enzymes and passive loss of these re-
Mehler: Epigenetics and the Nervous System
609
pressive marks.141,142 Changes in subunit composition
of chromatin remodeling complexes promote chromatin reorganization and permit neurogenic and gliogenic
signals to target neural transcription factors that promote neural subtype specification and maturation.137
The elaboration of neuronal and glial subtype specification and maturation, including myelination, also involves the differential actions of histone-modifying enzymes that promote histone acetylation and
deacetylation.143 During aging, further consolidation
of differentiation is promoted by epigeneticallymediated senescence-activated heterochromatic foci
(SAHF) to prevent inappropriate activation of proliferation or apoptosis in response to mitogenic cues, which
safeguards against the development of cancer and neurodegenerative diseases.127,144 ncRNAs, including miRNAs and other classes of ncRNAs, and RNA editing
are also essential for the epigenetic regulation of neural
lineage maturation from the stages of regional patterning of stem cell niches to progressive stem cell lineage
restriction, specification and maturation, and adult
neural plasticity responses.2,139
Epigenetics and Learning and Memory
Memory encoding, consolidation, storage, retrieval,
and reconsolidation involve local and system-wide epigenetic modifications.55,75,120,145–152 The interplay between primary DNA and histone modifications promotes transient and enduring profiles of synaptic and
neural network modifications.147,149 Memory consolidation is enhanced by changes in DNA methylation
through the actions of DNA methyltransferases and
demethylases acting at genomic sites to promote differential expression of synaptic plasticity and memory
suppressor genes.150 Specific histone modifications, including phosphorylation, acetylation, and methylation,
regulate long-term memory formation by modulating
promoters of plasticity-related transcription factors,
neurotransmitter receptors, cytoskeletal proteins, adhesion molecules, and metabolic factors.147,151 Memory
consolidation is further enhanced by gene modulation
through targeted histone modifications by alterations
in synaptic receptor-mediated intracellular signaling
pathways that integrate multiple environmental cues.4
Epigenetic modifications within selective gene networks may also play a role in learning and memory
through activation of adult neurogenesis.153,154
The molecular mechanisms responsible for converting a temporary memory trace into a long-term memory engram involve complex epigenetic mechanisms.155,156 Induction of the late phase of long-term
potentiation (LTP) facilitates integration of spatial,
temporal, and contextual information at dendritic subcompartments by synaptic “tagging” and “cross tagging” of informational inputs and through modulation
of plasticity-related proteins, transcription, post-
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transcriptional and post-translational processing, and
activity-dependent setting and resetting of these complex synaptic “tag” complexes. 76,155 Epigenetic tagging
during memory consolidation and maintenance involves complementary neurotransmitter-associated signaling pathways mediating different primary and linker
histone modifications, and also genome-wide chromatin remodeling, resulting in activation of immediate
early genes.4,147,148,151,152
The establishment of distinct memory states involves
differential protein translation from diverse and mobile
axodendritic mRNA pools.75,120,157 These translational
processes are orchestrated by RBPs, neuronal transport
granules, and the use of different modes of protein
translation through neuronal activity-dependent modulation of excitatory receptors and activation of mRNA
and ncRNA regulatory regions by gene modulators.46,55,75,120,121,145,158 ncRNAs can also modulate
local translation.2,48
Regulation of ncRNA transcription influences memory dynamics by altering the composition of higherorder chromatin complexes via direct regulation of
polycomb and trithorax group DNA regulatory elements.52 Excitatory receptors promote synaptic plasticity by directly regulating the kinetics of translocation of
neuronal granules and local mRNA translation.2,75,120,121,159 Activity-dependent signaling pathways also enhance long-term memory formation by
post-translational phosphorylation of neurotransmitter
receptors and concurrent histone modifications.4,120
The parallel phosphorylation of translation initiation
factors also represents an important linked regulatory
process mediating long-term synaptic plasticity and
memory consolidation.120 Epigenetic modulation of
the biophysical properties of protein: RNA: DNA
complexes represents additional mechanisms to orchestrate changes in activity-dependent signaling and neural network connectivity underlying memory formation.47,90
Synaptic plasticity encompasses an intermediate
phase associated with de novo protein synthesis from
pre-existing gene transcripts, and a late phase associated
with direct transcriptional modulation.120 During the
intermediate phase of synaptic plasticity, epigenetic
processes that affect mRNA stability, molecular complexity, and translation are activated, preferentially
those involving miRNAs and siRNAs and RNA editing.2,48,55,75,90,120,121 However, during the late phase
of synaptic plasticity, epigenetic mechanisms that regulate gene transcription and employ multiple posttranscriptional processes are selectively recruited.2,48
Plasticity-associated genes regulate the transcription of
several classes of ncRNAs, including miRNAs.2,55,75,120
ncRNAs are embedded within complex gene loci containing protein-coding genes, imprinted genes, and
other components of the epigenetic code that are
themselves regulated by changes in activity-dependent
signals to allow ncRNAs to orchestrate overall changes
in chromatin organization and the modulation of neural network plasticity and connectivity.2,48,160,161
The preponderance of Alu repetitive elements within
the human genome and the preferential role of RNA
editing in the nervous system suggest the possibility of
evolutionary co-adaptation, with Alu elements representing novel substrates for RNA editing and their selection as a mechanism to promote synaptic plasticity
and memory formation.90 ADAR- and APOBECmediated editing and recoding functions are functionally coupled, in part, though the actions of specific
classes of DNA polymerases/repair enzymes that possess intrinsic reverse transcriptase activity.162 In the
brain, this mechanism may allow retrograde trafficking
back to the nucleus of transient but salient environmentally-mediated “short-term” memory/ cognitive traces encoded via synapse-associated RNA editing
of specific profiles of transcripts. “Short-term” memories are then more permanently stored, consolidated,
and further processed as “long-term” memory/ cognitive traces by direct and even continuing recoding of the
neuronal epigenome.2,90 These RNA-directed DNA recoding events may be mediated by multiple molecular
mechanisms active in the nervous system: DNA repair
enzyme-associated reverse transcriptases, LINE-1 repetitive element-encoded reverse transcriptases in association
with different SINE/Alu repetitive elements, and programmed genomic rearrangements including RNAdirected DNA recombination.90,118,163–165 Within targeted neural networks, transformation of information
from a stimulus-based to a more abstract memory trace
may be mediated, in part, by different and evolving biophysical properties of reverse transcriptases coupling
RNA editing to DNA recoding.90,166,167 Examination
of RNA editing targets reveals that factors involved in
epigenetic modulation of synaptic plasticity and longterm memory, and in functional coupling of RNA editing and DNA recoding are also edited, suggesting additional degrees of flexible contextual modulation.90 Longterm plasticity mechanisms may also be subject to
multigenerational inheritance of complex cognitive traits
through somatic RNA transfer to the germline.90,123
Emerging Insights into the Early Diagnosis,
Pathogenesis and Treatment of Complex
Neurological Disease
Epigenetic mechanisms, including DNA methylation,
histone modifications, nucleosome and higher-order
chromatin remodeling, non-coding RNAs, RNA editing and DNA recoding, have been implicated in the
regulation of most cellular and molecular processes essential for higher nervous system functions. Accordingly, deregulation of these diverse epigenetic processes
has been associated with a broad spectrum of neuro-
logical and psychiatric disorders. In addition, the
emerging field of environmental epigenomics holds
great promise for identifying subtle and combinatorial
environmental risk factors responsible for promoting
the onset and progression of many diseases and for defining earlier and more selective biomarkers and molecular signatures of disease progression and responses
to therapy. A more complete discussion of epigenetic
processes in neurological and psychiatric diseases is presented in the supplementary material available online.
Environmental Epigenomics
The “epigenome” displays high degrees of plasticity
and heritability and represents the dynamic molecular
interface mediating gene-environmental interactions
throughout life (Fig 5).168 –171 Components of the
epigenome are unusually susceptible to disruption during gestation, the perinatal period, puberty and senescence.168,169 Complex environmental cues can modulate all major epigenetic processes: DNA methylation,
histone, nucleosome and chromatin remodeling,
ncRNAs, RNA and DNA editing, RNA trafficking and
dynamic genomic and nuclear reorganization2,90,169 –171
Metastable epialleles represent alleles with variable expression following epigenetic influences during early development; they are particularly susceptible to adverse
environmental influences that enhance susceptibility to
late-onset diseases.32,169 Dynamic epigenetic reprogramming during gametogenesis and in pre-implantation embryos is required to clear acquired epigenetic marks as a
result of genetic influences, environmental exposures
and disease states.31,35,168,169,172 Specific genomic sequences, including imprinted loci, heterochromatin
near centromeres and active repetitive elements, are
partially exempt from developmental epigenetic reprogramming.2,35,160,169,172,173 Imprinted genes are overly
represented at susceptibility loci for complex neuropsychiatric diseases, provide no buffer against adverse influences of recessive mutations, increase susceptibility
to developmental anomalies and disease states and
are deregulated by normally benign environmental
agents that can cause imprinting-associated gene allele
inactivation (“loss of heterozygosity” LOH) or inappropriate allelic expression (“loss of imprinting”
LOI).2,32,35,160,174 Multiple epigenetic processes can
enhance these and other potentially heritable changes.26, 32, 168,170,171,175 Environmental epigenetics has
significantly altered the concept of heritability to include environmentally mediated changes to the epigenome that are retained following mitosis, meiosis
and multigenerational transmission despite the absence
of direct inciting environmental events.32,168 –171,175 Environmental epigenomic initiatives will allow us to identify fine-grained and complex aversive environmental influences and to enhance the development of novel
epigenetic detection systems to identify sensitive biomar-
Mehler: Epigenetics and the Nervous System
611
∆ cellular
genetic
∆ environment
∆ epigenome
epigenotype
gametogenesis
∆ DNA methylation
imprinted genes
heterochromatin
∆ chromatin modifications
fertilization
∆ ncRNAs
active repetitive elements
DNA recoding
∆ RNA/DNA editing
∆ intracellular RNA transport
pre-implantation embryos
trans-neuronal/germline
RNA trafficking
metastable epialleles
neonatal
puberty
aging
heritable changes
phenotype
pre-clinical
phases
LOI / LOH
epimutations
recombination
genomic instability
neuropsychiatric
diseases
innovative neuroimaging/molecular
detection systems:
epigenetic biomarkers
signatures of pre-clinical states
disease progression
response to therapies
novel pharmacoepigenomic agents
Fig 5. Schematic representation of the mechanisms underlying environmental epigenomics and epigenetic influences throughout the
lifecycle, including postulated roles in phenotypic expression, heritability and in the pathogenesis, detection and progression and potential advanced treatment of neuropsychiatric disease states. Epigenetic processes represented in red illustrate those mechanisms under
complex cellular, genetic and environmental regulation (left-sided), those associated with dynamic epigenetic reprogramming during
key early developmental epochs (left-sided associated with arrows), those relatively resistant to developmental epigenetic reprogramming (right-sided) together with those that accumulate during later maturational stages (lower right side) and contribute to the evolution of neuropsychiatric diseases. LOH ⫽ loss of heterozygosity; LOI ⫽ loss of imprinting; ncRNAs ⫽ non-coding RNAs.
kers and complementary molecular signatures of disease
progression and incremental responses to therapeutic interventions to facilitate the development of innovative
pharmacoepigenomic tools to promote dynamic epigenetic reprogramming.168 –171
Therapeutic Implications: Pharmacoepigenomics
and Epigenetic Reprogramming
Three classes of epigenetic agents are currently utilized
in animal models of disease as well as in human clinical
trials: DNA methylation inhibitors, HDAC inhibitors
and RNA-based approaches.176 –178 DNA methylation
inhibitors exist as nucleoside and non-nucleoside analogues that can reactivate pathologically silenced
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genes.177,179 Nucleoside analogues act by demethylation or by removal of DNMTs, whereas nonnucleoside analogues act by binding to DNMT active
sites by preventing their expression without direct
DNA incorporation; the latter class is associated with
less cytotoxicity.177,179 Histone deacetylase inhibitors
include a broad spectrum of functional classes each
containing distinct biochemical modifications. Shortchain fatty acids are limited by low potency, specificity
and bioavailability; hydroxamic acids display higher
potency, less toxicity, a broader activity spectrum, actions on DNA demethylation and cooperativity with
other agents; benzamides exhibit higher bioavailability
including oral efficacy and synergy with numerous ad-
ditional agents; cyclic tetrapeptides directly block the
HDAC catalytic pocket, and hybrid agents containing
benzamides entitled cyclic hydroxamic acid-containing
peptides reversibly inhibit HDACs at low concentrations, and can create numerous independent molecular
species with unique functional properties by changes in
methylene chain length.177 Some psychotropic drugs,
including mood stabilizers, tricyclic antidepressants and
selective serotonin reuptake inhibitors function by
modifying HDAC activity and DNA methylationassociated enzymes.177 Transcription factors including
engineered zinc finger proteins that target specific gene
promoters can enhance the specificity of DNA methylation and HDAC inhibitors and avoid untoward effects associated with a lack of specificity.177 Additional
classes of DNA methylation and histone-modifying enzymes are being identified and rapidly employed using
advanced molecular library screening, high-resolution
structural imaging and associated pharmacoepigenomic
design techniques.177
Complementary approaches targeting RNA species
with short oligonucleotides acting on individual gene
transcripts under endogenous regulation can address
complex molecular mechanisms underlying neuropsychiatric diseases.176,178 Antisense oligonucleotides with
newer biochemical modifications to enhance stability,
specificity and efficacy are being applied to diseases
caused by epigenetic alterations associated with premRNA splicing.178 RNA trans-splicing to promote a
composite of two separately transcribed mRNAs using
“spliceosome-mediated trans-splicing” or “ribozymeassociated trans-splicing” is being utilized for epigenetic
diseases resulting from aberrant isoform switching, alterations of specific components of the epigenome or
even to promote RNA repair in situations in which
conformational changes subtly alter substrate/target
specificities for the actions of epigenetic enzymes,
ncRNAs or multiple DNA: RNA: protein interactions.178 RNA interference using double-stranded small
interfering RNAs is being examined for efficacy when
applied to distinct pathogenic lesions including enhancing the silencing of selective mRNA isoforms and
mutant alleles impaired by multiple epigenetic lesions.176,178 Additional modifications including
locked-nucleic-acid-modified oligonucleotides (LNAs),
“decoys” (short, double-stranded DNA molecules containing binding elements for a range of protein targets
that competitively inhibit promoter binding) and
“aptamers” (synthetic oligonucleotide ligands derived
by selection from a combinatorial library of nucleic
acid sequences that bind target proteins with high affinity and specificity) have the potential to combat
complex deregulated epigenetic targets including
ncRNAs, RNA/DNA editing enzymes and histone, nucleosome and chromatin remodeling factors.176,180,181
This work was supported by the NIH (National Institute of Neurological Disorders and Stroke grant number NS38902, National
Institute of Mental Health grant number MH66290, National Institute of Child Health and Human Development grant number
HD01799), the Roslyn and Leslie Goldstein, the Mildred and Bernard H. Kayden, the F. M. Kirby, the Alpern Family and the Rosanne H. Silberman Foundations.
I am grateful to Solen Gokhan and Irfan Qureshi for critical reading
of the manuscript and for inspired research initiatives and to John S.
Mattick and members of his laboratory group for creative collaborations, for the development of innovative conceptual frameworks in
the field of epigenetics and epigenomic medicine and for sharing of
scientific information prior to publication. I regret that space constraints have prevented the citation of many important primary and
secondary source materials.
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