Download Gender and epigenetics - Association for Contextual Behavioral

Learning in heredity and evolution:
an epigenetic perspective
ACBS, Eva Jablonka July 2013
What is epigenetics, epigenetic inheritance and are
epigenetic mechanisms?
Psychiatric epigenetics; the epigenetics of learning
Epigenetic transmission of acquired behavioral
dispositions
Some evolutionary implications (early evolution)
Epigenetics
The science of enduring changes in the pattern of gene
activity, during embryo development and beyond, that
do not involve alteration of the DNA sequence. These
changes occur in response to conditions within the
embryo and more generally. (Mark Pemberey)
Epigenetics is the study of developmental processes [in
prokaryotes and eukaryotes] that lead to persistent, selfmaintaining, changes in the states of organisms, the
components of organisms, or the lineages of organisms
(Jablonka and Lamb)
Different Cell Types with the Same DNA
Genetically identical
Endocrine system mediating temperature-dependent
polyphenism: Bicyclus
Low
ecdysone
High
ecdysone
Predator-induced Polyphenism: Daphnia
Miyakawa, H. et al . 2010. Gene up-regulation in response to kairomones in the waterflea Daphnia pulex. BMC
Developmental Biology 10:45. Hox3, extradenticle and escargot
Epigenetic inheritance
Epigenetic inheritance is a component of epigenetics. It
occurs when phenotypic variations that do not stem from
variations in DNA base sequence are transmitted to
subsequent generations of cells or organisms.
It is used in a broad and a narrow (cellular) sense.
Epigenetic inheritance
Epigenetic inheritance is a component of epigenetics. It
occurs when phenotypic variations that do not stem from
variations in DNA base sequence are transmitted to
subsequent generations of cells or organisms.
It is used in a broad and a narrow (cellular) sense.
Cellular epigenetic inheritance
Cellular epigenetic inheritance is the transmission from mother cell to
daughter cell of variations that are not the result of differences in DNA base
sequence or the present environment. The cell is the unit of transmission.
Transmission can be through
• self-sustaining metabolic loops
• self-reconstructing three-dimensional structures
• chromatin marks
• RNAs
It occurs during cell division in prokaryotes, mitotic cell division in the soma of
eukaryotes, and sometimes during the meiotic divisions in the germline. Jablonka
and Raz (2009) found over 100 studies of transgenerational cellular epigenetic
inheritance. Many more studies were published since.
Chromatin variations
Figure 1: Mechanisms involved in chromatin modification
Catherine Dulac Nature 465:728–735, 2010
doi:10.1038/nature09231
Replication of two DNA methylation patterns
Jablonka & Lamb Evolution in Four Dimensions 2005, p. 129
RNA silencing and its transmission
Disease-associated epigenetic changes in
monozygotic twins discordant for schizophrenia
and bipolar disorder
Dempster et al 2011 Human Molecular Genetics, 2011, Vol. 20, No. 24 4786–
4796
Numerous loci demonstrated disease-associated DNA
methylation differences between twins discordant for SZ
and BD individually, and together as a combined major
psychosis group. Pathway analysis of our top loci
highlighted a significant enrichment of epigenetic changes
in biological networks and pathways directly relevant to
psychiatric disorder and neurodevelopment. .
Overall, our data provide further evidence to support a
role for DNA methylation differences in mediating
phenotypic differences between MZ twins and in the
etiology of both SZ and BD.
Methylomic analysis of monozygotic twins discordant for
autism spectrum disorder and related behavioural traits
Wong et al 2013, Molecular Psychiatry (2013), 1–9
We performed a genome-wide analysis of DNA methylation
in a sample of 50 MZ twin pairs (100 individuals) sampled
from a representative population cohort that included twins
discordant and concordant for ASD, ASD-associated traits
and no autistic phenotype. Within-twin and between-group
analyses identified numerous differentially methylated
regions associated with ASD. In addition, we report
significant correlations between DNA methylation and
quantitatively measured autistic trait scores across our
sample cohort. This study represents the first systematic
epigenomic analyses of MZ twins discordant for ASD and
implicates a role for altered DNA methylation in autism.
Epigenetic regulation of the glucocorticoid receptor in human
brain associates with childhood abuse
Patrick O McGowan, Aya Sasaki, Ana C D’Alessio, Sergiy Dymov, Benoit Labonte´, Moshe Szyf,
Gustavo Turecki & Michael J Meaney
Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the
rat through epigenetic programming of glucocorticoid receptor expression. In
humans, childhood abuse alters HPA stress responses and increases the risk
of suicide. We examined epigenetic differences in a neuron-specific
glucocorticoid receptor (NR3C1) promoter between postmortem
hippocampus obtained from suicide victims with a history of childhood
abuse and those from either suicide victims with no childhood abuse or
controls. We found decreased levels of glucocorticoid receptor mRNA,
as well as mRNA transcripts bearing the glucocorticoid receptor 1F
splice variant and increased cytosine methylation of an NR3C1
promoter. Patch-methylated NR3C1 promoter constructs that mimicked
the methylation state in samples from abused suicide victims showed
decreased NGFI-A transcription factor binding and NGFI-A–inducible
gene transcription. These findings translate previous results from rat to
humans and suggest a common effect of parental care on the epigenetic
regulation of hippocampal glucocorticoid receptor expression.
Fear Conditioning
Epigenetic changes in a rodent model of
post-traumaticstress disorder (PTSD). (a)
In Roth et al.,57 PTSD was modeled in
rats using two unpredictable and
inescapable exposures to a cat, in which
the rat was enclosed in a plexiglass
container while the cat circled above for 1
h. Effects of trauma were enhanced by
social instability in the stressed animals,
which consisted of changing the animal’s
cagemate daily for all 31 days of the
experiment while control animals had a
stable cagemate throughout the
experiment. (b) Bisulfite sequencing PCR
demonstrated region-specific effects of
stress on Bdnf at exon IV in the
hippocampus. Increases in methylation
were found in the dentate gyrus and CA1
of the dorsal hippocampus, whereas
decreased methylation was found in CA3
of the ventral hippocampus
Trans-generational effects that by-pass the germ
line (soma-soma, experience-dependent)
Trans-generational effects
Soma-to-soma Transmission: Maternal
behaviour in the rat
Environmental programming of gene activity
Glucocorticoid receptor gene
LOW LG
PUP (Day 1-6)
HIGH LG
ADULT (Day 90)
GR GENE
GR GENE
GR RECEPTORS
GR RECEPTORS
STRESS RESPONSE
STRESS RESPONSE
Putative promoter sites of genomic GR
GR GENE
11
PUTATIVE PROMOTER SITES
14
15 16 17 18 19 110
111
2
1681
ccc
1741 ctctgctagt gtgacacact t1cg2cgcaact c3cgcagttgg 4cggg5cg6cgga ccacccctg7c
1801 ggctctgc8cg gctggctgtc accct9cgggg gctctggctg c10cgaccca11cg ggg12cgggct
1861 c13cgag14cggtt ccaagcct15cg gagtggg16cg gggg17cgggag ggagcctggg agaa
NGFI-A
(McCormick J.A., Mol Endo. 2000)
Transgenerational Rescue of a Genetic Defect in Long-Term
Potentiation and Memory Formation by Juvenile Enrichment
Junko A. Arai, Shaomin Li, Dean M. Hartley, and Larry A. Feig
…Here, we demonstrate that exposure of 15-d-old mice to 2 weeks of an enriched
environment (EE), that includes exposure to novel objects, elevated social interactions
and voluntary exercise, enhances long-term potentiation (LTP) not only in these
enriched mice but also in their future offspring through early adolescence, even if the
offspring never experience EE. In both generations, LTP induction is augmented by a
newly appearing cAMP/p38 MAP kinase-dependent signaling cascade. Strikingly,
defective LTP and contextual fear conditioning memory normally associated with
ras-grf knock-out mice are both masked in the offspring of enriched mutant
parents. The transgenerational transmission of this effect occurs from the enriched
mother to her offspring during embryogenesis. If a similar phenomenon occurs in
humans, the effectiveness of one’s memory during adolescence, particularly in those
with defective cell signaling mechanisms that control memory, can be influenced by
environmental stimulation experienced by one’s mother during her youth.
Good system for testing for epigenetic inheritance
Gametic Epigenetic inheritance
Linaria
Wild-type
Epimutant
Germline transmission of vinclozolin-induced changes
Jirtle and Skinner 2007
Vinclozolin treatment has trans-generational effects
on mate preference
April 2007, PNAS
David Crews, Andrea C. Gore, Timothy S. Hsu, Nygerma L. Dangleben, Michael
Spinetta, Timothy Schallert, Matthew D. Anway, and Michael K. Skinner
Changes in the methylation pattern of many genes is involved.
Heritable epigenetic changes are called epimutations.
Epigenetic Transmission of the Impact of Early Stress Across Generations
BIOL PSYCHIATRY 2010;68:408–415
Tamara B. Franklin, Holger Russig, Isabelle C. Weiss, Johannes Gräff, Natacha Linder,
Aubin Michalon,Sandor Vizi, and Isabelle M. Mansuy
Background: Traumatic experiences in early life are risk factors for the development of behavioral
and emotional disorders. Such disorders can persist through adulthood and have often been
reported to be transmitted across generations.
Methods: To investigate the transgenerational effect of early stress, mice were exposed to chronic
and unpredictable maternal separation from postnatal day 1 to 14.
Results: We show that chronic and unpredictable maternal separation induces depressivelike behaviors and alters the behavioral response to aversive environments in the separated
animals when adult. Most of the behavioral alterations are further expressed by the
offspring of males subjected to maternal separation, despite the fact that these males are
reared normally. Chronic and unpredictable maternal separation also alters the profile of
DNA methylation in the promoter of several candidate genes in the germline of the
separated males. Comparable changes in DNA methylation are also present in the brain of
the offspring and are associated with altered gene expression.
Conclusions: These findings highlight the negative impact of early stress on behavioral
responses across generations and on the regulation of DNA methylation in the germline.
Methylation of the CpG island surrounding the
transcription initiation site of MeCP2 and CB1 genes
was increased in F1 MSUS sperm (Figure 5A, 5C, 5E,
5G). In contrast, for the CRFR2 gene, methylation in a
stretch of the CpG island located 5- of the transcription
initiation site was decreased (Figure 5I and K).
Methylation was not changed in target regions
of the 5-HT1A or MAOA gene (Supplement 1, Figure
S4). These data indicate that DNA methylation is
altered in both directions and in a gene-specific
manner in the germline of males subjected to early
stress. Because they are present in the germline, the
changes in DNA methylation could potentially be
maintained and transmitted to the following generation.
To test this hypothesis, we checked the profile of DNA
methylation of the candidate genes in the brain of the
female F2 progeny. Strikingly, a similar
hypermethylation of the same stretch of CpGs was
observed in both the MeCP2 and CB1 genes (Figure
5D and 5H) and a hypomethylation of CRFR2 CpG
island (Figure 5L). These changes in methylation were
functionally relevant because they
were associated with a decrease in the level of mRNA
expression of these genes (Figure 5B, 5F, 5J).
Cannabinoid receptor-1 (CB1),
associated with emotionality in rodents;
corticotrophinreleasing factor receptor 2 (CRFR2), a
stress hormone receptor;
MeCP2 – control of stress, Rett syndrome.
MAOA role in depression, and an enzyme that
catalyzes the degradation of serotonin
WIREs Cogn Sci 2013, 4:105–115. doi: 10.1002/wcs.1205
Human persistent pollution
Religious wars: chronic stress
Evolution
Learning and evolution
The Baldwin effect:
learning-adaptation first, genetic changes follow (stabilize, facilitate etc. the learnt
response).
Drives the evolution of learning itself including motivational, sensory and motor
aspects of behavior in the focal species and in interacting species.
Drives morphological adaptations (e.g. defenses)
Leads to both increased canalization (buffering) and increased developmental
plasticity.
The evolutionary sophistication of learning and memory led to major transitions in
animal evolution.
Associative learning drove the Cambrian explosion
The evolution of symbol based-learning (linguistic communication and
representation) in hominins.
When did associative learning (AL) evolve?
Why was it selected? what were the evolutionary effects?
Distribution of AL: all vertebrates and several groups of
invertebrates
AL was the adaptability driver of the Cambrian explosion
The evolution of AL led to ecological arms races, evolution of sensory modalities,
learning etc. through the Baldwin effect.
It led to ongoing stress (the smoke detector principle) and this enhanced generation of
variations (until more efficient whole-organism stress responses evolved)
Predictions: the bifurcation leading to nephrozoans was characterized by the
appearance of new neural/learning-specific pfams and MiRs (preliminary results support
this conjecture).
The evolution of lanaugage