Molecular Basis of Neuropsychiatric Disorders (ANAT0012) Complete Notes
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Course
ANAT0012 (ANAT0012)
Institution
University College London (UCL)
Complete notes and all additional reading for the module including textbook notes, assigned reading, and extended reading. Evidence and research papers allocated in tables and broken down into background, aims, methods, results, conclusions, and critical thinking. Broken down into chapters and subc...
ANAT0012
MOLECULAR BASIS OF NEUROPSYCHIATRIC DISORDERS
,Epigenetics
GENE EXPRESSION
- Cells use info in genes to build different proteins each with a unique function
- DNA mRNA protein
- Not all proteins are required by the cell at any one time. By regulating gene expressions, cells control when
each protein is made
GENE STRUCTURE
- Promoter: region of DNA that initiates transcription of a particular gene
o Regulates where, when and to what level a gene is expressed
- Accessibility to the promoter by the transcriptional machinery is key --> this is where the transcriptional
machinery comes in and transcribes the DNA to mRNA
Chromatin remodeling exposes the promoter
- Chromatin: combination of DNA and other proteins that make up contents of nucleus
o Condensed = transcription OFF
Transcriptional repressors recruit corepressor complexes, causing histone modifications,
leading to chromatin remodelling
Bind to promoters to impede subsequent binding of RNA polymerase
o Relaxed = transcription ON
- Epigenetic mechanisms are the mechanisms of chromatin compaction
o Chromatin remodeling: regulatory transcription factors recruit chromatin-remodeling complex or
HATS. Chromatin decondenses
Dynamic process throughout lifetime and exposure is crucicial in initiation of transcription
o Exposure of promoter: when chromatin decondenses, a region of DNA is exposed including the
promoter
- Epigenome: shapes structure of genome
o Flexible – changes throughout life
o Epigenetic tags react to signals from outside world and adjusts specific genomes in genomic
landscape in response to changes in environment
EPIGENETICS
INTRO
Ryan, Saffery and Patton, 2018
- Epigenetic modifications regulate gene activity in response to encironmental cues WITHOUT alteraltations to
the DNA sequence
- Active in early life with epigenome affecting growth trajectories and later cardio-metabolic risks (Gluckman
et al., 2009)
- Epigenetic changes in glucocorticoid system alter PTSD and anxiety disorders --> role in later psychiatric
disorders (de Quervain et al., 2017)
Conrad Waddington
- Epigenetic landscape in early 1940s
- To elucidate diverse programming of the single genome to create different cells of multicellular organisms
during the development
- How can a single cell develop and differentiate into many types using only single DNA
However
, - Epigenetic regulation is complex, dynamic with many functions other than their role on developmental
programming
- Epigenome interacts with the micro and macro environment
- Help adaptation ot the ever-changing conditions in an age and generation specific manner
EPIGENETIC MECHANISMS: CHROMATIN REMODELING
1. DNA methylation
a. Longer lasting
b. Adding CG bases
c. Regulates compaction of DNA
2. Histone Modifications
a. Post-translational modification
3. RNA based mechanisms
a. miRNAs
i. Expression of micro RNAs
ii. Small RNAs not turned into proteins
iii. Used in gene expression regulation by removing proteins (leads to protein destruction but
not change in chromatin compaction)
DNA METHYLATION
Significance
- High degree of DNA methylation usually implies inhibition of gene expression
o Higher DNA methylation, less likely the transcription factors can bind, and the more likely ____
- Location of methylation matters
, o
- Usually, DNA methylation at the promoter sequence or upstream CpG island correlates with the level of
expression of a gene
HISTONE MODIFICATIONS
1. Proline isomerization
2. Phosphorylation
3. Methylation
a. Recruitment of methyl binding ptoyrin
b. Recruits HDAC which impact on post-translation modification on histones
4. Acetylation
a. Acetylated = transcription likely to occur
5. Ubiquitination
RNA BASED MODIFICATIONS
miRNA: RNA editing and RNA interference
- Noncoding miRNAs are the most significant epigenetic regulators discovered in the last decade
- 18-25 pb long
- Target mRNAs for degradation or suppress protein synthesis less/no protein is made
- Many enzymes responsible (histone deacetylases/DNA methyl transferase) are under control of miRNAs
linked to epigenetic mechanisms
- Each small miRNA can target hundreds of different genes and each gene may be the target of several
miRNAs
- RNA-based mechanisms have recently been shown to impact the higher-order structure of chromatin such
as small noncoding RNAs
miR-124-3p (Roy et al., 2017)
The neuron-specific miR-124-3p affects stress response genes and neural plasticity (Roy et al., 2017)
- Under epigenetic control
- Overexpressed in prefrontal cortex in rodent models of depression (Roy et al., 2017)
- MDD: upregulated in prefrontal cortex (postmortem, 15 cases, 15 controls) and serum (18 cases, 17
controls) compared with controls without a history of mental disorders
Anti-depressant treatment response in MDD
- 4 miRNAs were downregulate din the blood of responders (n=151) compared with non responders (n=107)
after 8 weeks of treatment (Lopez et al., 2016)
- Suggests that specific miRNAs might be novel targets in drug development and monitoring of treatment
effectiveness
- miRNAs 146a/b-5, 425-3p and 24-3p are markers of antidepressant response and regulate MAPK/Wnt-
system genes
IMPORTANCE IN INVESTIGATING EPIGENETIC MECHANISMS
- Understand the neurobiology
- Identify risk factors
, - Establish biomarkers (make up for hard to quantity features like behaviour)
- Generate novel therapeutic interventions
TWIN studies: instrumental in elucidating the contribution of epigenetics
Fraga et al., 2005
- Same DNA sequence, same genes, susceptible to the same diseases
- Mapping of chromosomal regions with differential DNA methylation
o Yellow: at the same place
o Red/green: different place
-
- Even though they have the same genes, the way the genes are regulated differs between the individuals
- Use twin studies to assess the contribution of the 2 factors (genetics vs epigenetics) to a specific traight
o E.g., panic disorders are twice as frequent in MZ than DZ --> disease mainly caused by genetic
factors
DIFFICULTIES WITH EPIGENETIC ANALYSIS IN NEUROPSYCHIATRIC DISEASES
- Epigenetic codes are dynamic, tissue, and cell type specific
- Access to brain tissue is difficult
- Psychiatric studies limited to postmortem brain tissue or blood/saliva
- BUT
o Recent GWAS studies indicate that the correlation between the blood and brain methylome is high
or adequate
o Animal models
- However, always ask whether the tissue sampled is a suitable surrogate for the affected brain cells
Epigenetics might provide insights into a discordance between high heritability and the few genetic variants
associated with the disease
METHODS – GWAS AND MWAS – BLOOD AS SURROGATE TISSUE
GWAS vs MWAS:
- Methylation can be tissue specific and analyses are ideally performed in the most relevant disease tissue
- In psychiatric diseases, postmortem tissue is the only option
o Small number of samples and clinical info is limitated and confounding factors as cause of death can
distort methylation profile
- Blood is the typical tissue used in methylation studies of psychiatric conditions
o There is little known about the usefulness of blood as proxy for brain tissue in MWAS
,Blood in MWAS (Aberg et al., 2013)
- Blood is the typical tissue used but little is known about its usefulness
- There are two models explaining how blood could be informative
o Signature model: factors that affect brain processes leave signatures in the blood
Associatiation between methylation in blood and disease occurs dbecause a disease-related
event alters methylation site
Traces of the event are preserved and can be detected in the blood
Although the sites where methylation changes occur (DMPs) do not affect the psychiatric
conditions, they implicate an event that contributed to the disease
o Mirror-site model: methylation status of DMPs in the blood can mirror those in the brain
Association occurs because the methylation status of a site in the blood is correlated with a
corresponding site in the brain that may be of relevance for the disease etiology
Peripheral tissues may reveal methylation marks rpedating or resulting from the epigenetic
reprograming events affecting germ line cells and embryogenesis
Blood contains cells that can be modified as they circulate through diseased tissues
Traces of aberrant methylation in disease-targeting regions may be present in the blood
- Aim: study the plausibility of the two models
- Method
o Performed methylome-wide profiling using 3 tissues (blood, cortex, hippocampus) from 14 male
C57BL/6 mice
o 4 of the mice were administered highly potent anti-psycohotic haloperidol
Affects processes in brain
Associated with global changes in methylation (Melas et al., 2012)
Purpose of ttreatment is not to specifically study effect of haloperidol but to induce a
methylation change and investigate if there is an overlap in effect in different tissues
o Remaining 10 mice were untreated
o Mice raised in control environment with minimal variation
o 3 tissues from mice collected at a single time point – all mice were same age and inbred mouse
strain used so methylation differences were minimal
Maximises statistical power to detect induced changes and study correspondence of
subsequent changes in blood and brain
o Used methyl-binding domain enrichment and NGS o
- Results: despite treatment inducing large number of methylation changes, the correlation remains high
o Treatment affected methylation in a large number (42.4%) of CpG sites
Changes were not limited to brain tissue (21.1% of sites changed in blood)
Suggests that factors that are strongly associated with brain function may leave methylation
signatures in the blood
o 9% of the sites were DMP in the blood but not brian tissues
In agreement with signature model, the methylation status of specific sites detected in
blood may act as biomarkers for psychiatric conditions
- Conclusion: results showed that, consistent with signature model, factors that affect brain processes leave
biomarker signatures in the blood and, consistent with mirror-site model, the methylation status of many
sites in the blood mirror those in the brain
o Support the use of blood as a surrogate tissue
-
,EXAMPLE 1: AUTISM SPECTRUM DISORDER (ASD)
Definition: heterogeneous group of neurodevelopmental disorders characterized by problems with social
communication, social interaction, and repetitive or restricted behaviours
- Currently defined on basis of behavioural observations only
- Other features include
o Attention deficits
o Sensory and motor abnormalities
o Cognitive impairment and epilepsy
o ASDs involve the frontal, temporal, and occipital lobe cortices and the cerebellym
- Genes associated with ASD
o Major gene network: neurodevelopment/cell signalling
o Half of the genes are related to epigenetic mechanisms
- Recently, postmortem brain samples and blood samples have indicated that epigenome alteractions are
linked to pathogenesis of ASD
o ASDs are thought to results from disordered neurodevelopment
o Does it mean that the epigenetic alteration are there from birth?
o Does epigenetic state mediate the cause of or result from the disorder?
Epigenetic Studies in ASD
- A number of epigenetic changes have been linked with ASDs
- But ASDs are though to result from disordered neurodevelopement
- Does it mean that epigenetic alterations are there from birth?
- Alterations happen in utero environment?
1. Methylation analysis of ASD candidate genes (Loke et al., 2015) changes in DNA methylation in
candidate genes have been identified!!!
a. Oxytocin receptor (OXTR): GPCR; plays a role in anxiety, social memory, recognition
i. 23-39% higher DNA methylation in ASD at specific CpGs
ii. Higher methylation correlated with lower OXTR expression in temporal cortex
b. Glutamate decarboxylase 1 (GAD1): Encodes an enzyme that catalyses the production of GABA
(inhibitory NT) from glutamate
i. Genetic evidence is small
ii. 3% increase in DNA methylation at the GAD1 promoter in cerebella from ASD patients
c. Engrailed-2 (EN2): Encodes a protein implicated in the control of pattern formation during
neurodevelopment
i. EN2 promoter: 10-20% increased DNA methylation in ASD cerebella
, ii. DNA methylation negatively correlates with RNA and protein levels
d. Reelin (RELN): Secreted extracellular matrix glycoprotein involved in neuronal migration and
positioning in the developing brain and modulates synaptic plasticity in the adult brain
i. Increased levels of DNA methylation in cerebella from ASD patients
ii. Lower levels of RELN
e. MeCP2
2. Methylation analysis in epigenome-wide studies
a. Epigenome Wide Association Studies (EWAS)
b. Look for differentially methylated regions (DMRs)
c. Best case scenario: when methylation correlates with expression of a nearby gene that has relevance
for the specific disorder
d. Two differentially methylated gene pathways have been highlighted
i. Neurodevelopment
ii. Immune and inflammatory response
e. Analytical methods need to be standardized to reach valid conclusions
EXAMPLE 2: PSYCHOSIS DISEASES (PTSD)
Bipolar disorders: a condition that affects your moods – extreme swings
Schizophrenia: a psychiatric disorder – continuous or relapsing episodes of psychosis. Hallucinations ----
Abdolmaki et al., 2015: review
- Genetic studies alone are yet to uncover major genes for psychosis (bipolar disorder, BD and schizophrenia,
SCZ)
- Genome Wide Association Study (GWAS): discovery of susceptibility genes (associated with schizophrenia,
bipolar disorder and other mental diseases but only increase the disease risk by less than 1%)
- No single gene clearly identified
- The alternative: looking at epigenetic modifications and modifier
Recently, post mortem brain samples and blood samples have indicated that:
- Aberrant DNA methylation
- Histone modifications
- Dysregulation of miRNAs
are linked to the pathogenesis of psychotic diseases
Aberrant Histone Modifications in Psychotic Disorders
- Not as much studied as changes in DNA methylation
- There are reports of abnormal histone modifications in psychotic disorders. E.g.:
o Post mortem brain samples; decreased acetylation of H3K9K14 at the promoter of GAD1 which is
involved in SCZ pathogenesis
- But most of the data point to the importance of HDAC regulation in the brain of individuals affected with
psychotic disorders. E.g.:
o Dysregulation of HDAC3 in the temporal cortex
o Increased expression of HDAC1 in the frontal cortex of SCZ patients
- Therapeutic agents that modulate histone codes have been in the forefront of experimental remedies for
BD and SCZ. E.g:
o Valproate best known nonspecific HDAC inhibitor, used to increase H3 acetylation
o Some antipsychotic drugs (e.g. MS275) also exhibit HDAC inhibitory effects
In conclusion, aberrant histone modifications may be involved in the pathogenesis of psychotic disorders and on,
the most effective drugs in major psychiatric diseases may act by targeting histone codes!
Epigenetics + psychiatric conditions – WHY IS IT IMPORTANT?
1. Biomarkers?
a. Personalized medicine emphasizes focus on finding reliable biomarkers for psychiatric disorders
, b. Peripheral epigenetic markers predictive of disease onset is particularly interesting
c. Blood DNA methylation patters were identified that were associated with transition to psychosis in
young adults at high risk (Kebir et al., 2017)
2. Evidence of intergenerational transmission of environmentally acquired risks via the germline
a. Guinea pigs exposed in utero to synthetic glucocorticoids had offspring with altered cortisol
responses to stress and stress-related behaviours effects continued into subsequent generation
(Moisiadis et al., 2017)
b. Short et al., 2017 showed that exercise in the father reduced anxiety behaviours in male but not
female offspring + changed the small non-coding RNA profile in mouse sperm
c. Study of Holocaust survivors showed higher levels of FKBP5 methylation in blood cells (control
glucocorticoid receptor signaling) compared with unexposed controls + adult offspring had
significantly lower levels of FKBP5 methylation (Yehuda et al., 2016)
i. The environment = stress, diet, etc cannot be simply attributed to the stressful conditions
but couldn’t it also be attributed to lack of nutrients in the diet?
2. Knowledge of methylation status of gene can aid in prediction of disease susceptibility
a. Aberrant methylation associated with human phenotypes including neurological and psychiatric
disorders
b. Methylation helps us to further understand psychiatric disorders
i. Studies have linked estrogen to chromatin configuration and DNA methylation profiles at
specific loci in the genome (Jost et al., 1991; Yokomori et al., 1995)
1. Suggests that sex differences observed in psychiatric conditions may be partially
mediated by epigenetic processes (Kaminsky et al., 2006)
ii. Methylation can be age dependent (Cooney et al., 1993) and is dynamic in postmitotic tissue
in the brain (Miller et al., 2007)
1. May account for different ages of onset or episodic nature of some psychiatric
diseases (Bjornsson et al., 2004)
3. Methylation sites are potential new drug targets
a. Methylation sites are modifiable by pharmaceutical interventions and have good properties from a
translational perspective
i. Stable, cost-effect assays, easy to collect
Problems – Critical Thinking
- Caution needed in translating animal studies into human context
- Inability to disentangle environmental exposure via epigenetic modifications from other sources of parent-
offspring transmission cannot be easily resolved
- Multifaceted integrative analysis essential
o Facilitated by availability of publicly accessible gene expression and epigenetic data for tissues and
disease state + animal models + functional assays + preclinical model systems
, EXAMPLE 2A: EPIGENETIC CHANGES IN PTSD
PTSD: exposure to traumatic event that involves actual or threatened death, serious injury or sexual violence from
- Directly experiencing the trauma
- Witnessing the events occur to others
- Learning that traumatic events occurred to close family member
- Experiencing repeated exposure
Pre-Clinical Models of PTSD
- The neural circuit involved in fear and anxiety is highly conserved throughout evolution
- Fear conditioning: predator smell, foot shock, associated with noise
Evidence of Epigenetic Changes in PTSD
1. Meaney et al., 2004: epigenetic programming by maternal behaviour
Backgroun - Maternal effects influence defensivge responses to threat in organisms
d - Maternal behaviour is the basis for transmission of individual differences in the
stress response from mother to offspring
- Offspring of high licking/grooming (LG) and arched back nursing (ABN) less
fearful and more modest HPA responses to stress than offspring of low-LG-ABN
mothers
- Cross-fostering studies
- Findings suggest variations in maternal behaviour as mechanisms for nongenomic
transmission of individual differences
Aim Determine whether increased LG and ABN by rat mothers altered offspring epigenome
Method
Results
Conclusions
2. M. Meaney: postmortem human brain tissue
o Association between methylation status of the orthologous exon 1F promoter region in human
NR3C1 in the hippocampus and history of childhood trauma
McGowan et al., 2009
o GRs help regulate stress
o Decrease GR expression in patients that committed suicide but were exposed to trauma and abuse
in early life
o Increase DNA methylation of NR3C1 promoter for suicide abused patients --> lower chance of
expression of gene
o Some association in whole blood samples
Tyrka et al., 2012
3. Monsey et al., 2011: training-regulation of histone H3 acetylation and DNMT3A expression in the LA is
specific to tone shock pairing
Title: Epigenetic Alterations Are Critical for Fear Memory Consolidation and Synaptic Plasticity in the Lateral
Amygdala
Key points:
- Epigenetic mechanisms including histone acetylation and DNA methylation have been widely implicated in
hippocampal dependent learning paradigms
- Study examines role of epigenetic alterations in amygdala dependent auditor Pavlovian dear conditioning and
associated lateral nucleus of the amygdala synaptic plasticity in the rat
- Show that fear conditioning is associated with an increase in histone H3 acetylation and DNMT3A expression in
the LA
- Some other findings. See paper for more detail but…
- Collectively findings provide strong support that histone acetylation and DNA methylation work in concert to
regulate memory consolidation of auditory fear conditioning and associated synaptic plasticity in the LA
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