I will argue that
Table of Contents
Part I: Introduction – Basic Definitions and Concepts................................................................................1
Part II: Epigenetic Mechanisms: Mechanisms of Chromatin Remodelling..................................................1
Part III: Difficulties with Epigenetic Analysis in Neuropsychiatric Diseases................................................2
Part IV: Autism Spectrum Disorders (ASD).................................................................................................3
Part V: Psychotic Disorders – PTSD, BD, and SCZ.......................................................................................4
Epigenetics of PTSD...............................................................................................................................................4
Epigenetics of Depression......................................................................................................................................9
Part VI: MeCP2 and Rett Syndrome.........................................................................................................10
Part I: Introduction – Basic Definitions and Concepts
Gene Expression
Cells use information in genes to build hundreds of different proteins, each with a unique function
Although every cell in the body contains the same DNA, they do not present with the same mRNA profiles and
do not express the same proteins
This is because gene expression is tightly regulated, so that proteins expressed in a subset of cells are
expressed in a timely manner/tissue specificity
Gene Structure
DNA is read from the 5’ to 3’ end
Promoters are key DNA regions important for the regulation of gene expression – this is where transcription of
a particular gene is initiated
o They regulate where, when and to what extent a gene is expressed
o Promoters are not active in every single cell
The 3D conformation of the DNA is important for the accessibility of TFs to the promoter region
DNA is wrapped around histones (chromatin)
Both the DNA and histones are covered with chemical tags (the epigenome)
The epigenome shapes the physical structure of the genome
o It tightly wraps inactive genes – making them unreadable (so TFs cannot bind to their promoters)
o It relaxes active genes, making them easily accessible
The epigenome is flexible – epigenetic tags react to signals from the outside world (e.g., diet, stress)
Epigenetics
Epigenetics were first described in the early 1940s by Waddington
He described epigenetic mechanisms as mechanisms necessary to understand how diverse programming of
the single genome can create different cells of multicellular organisms during development
o They “secure” the faith of a cell subtype
Epigenetic regulation is complex and dynamic, with many functions other than their role on developmental
programming
The epigenome interacts with the micro (e.g., hormones, NTs, neuronal activation/inhibition) and macro
(nutrition, drugs, pollution, etc.) environment
o Environment can influence gene expression through chromatin remodeling
This helps adaptation to the ever-changing conditions in an age and generation specific manner
Part II: Epigenetic Mechanisms: Mechanisms of Chromatin Remodelling
DNA Methylation
High degree of DNA methylation usually implies inhibition of
gene expression
The location of the methylation matters!
o Usually, DNA methylation at the promoter sequence or
upstream CpG islands correlates with the level of
expression of a gene
o The more these are methylated, the less likely the gene
will be expressed
, o Methylation at the promoter region inhibits the binding of TFs
o NB: there are other regions (e.g., enhancers) that are also important in the regulation of gene
expression
o Even though they seem far from a gene itself in a 2D structure, the 3D conformation of the DNA can
make these regions close to the actual gene
Histone Modifications
We understand very well how all the histones can be modified and their impact on gene expression
o There are a lot of possible histone modifications
o They could be on different histone proteins
o They could be on different amino acids
o They could be different modifications: phosphorylation, acetylation, methylation, ubiquitination, etc.
There are many enzymes responsible for specific modifications on specific amino acids in a
protein
Acetylation adds a -ve charge & the DNA backbone is also -vely charged, so acetylation leads to relaxation of
chromatin
These changes can be reversed – for example, HDACs (histone deacetylases remove the acetylation and
lead to the compaction of chromatin 🡪 less transcription
Different modifications have different effects on the compaction of chromatin
NB: histone modifications and DNA methylation are NOT completely independent mechanisms
o This is because when DNA is methylated, this gives the opportunity for DNA binding proteins to bind
onto methylated DNA, which can in turn recruit other proteins that can modify histones
o This happens very often
miRNA: RNA editing and RNA interference
miRNA = micro-RNA
o 18-25bp long
o They are non-coding
o More than 1000 miRNAs bind to different target mRNAs and induce RNA degradation or suppress
protein synthesis.
miRNAs are often discussed as epigenetic mechanisms because they are mechanisms of gene expression
regulation above the genome (i.e., without changing the DNA sequence)
Non-coding miRNAs are the most significant “epigenetic regulators” discovered in the last decade
They target mRNAs for degradation OR they suppress protein synthesis
o Essentially, they make sure that the targeted mRNAs are never made into a protein
Each miRNA can target hundreds of genes and each gene may be a target of several miRNAs
RNA-based mechanisms have been identified to be able to modify the higher-order structure of chromatin
Part III: Difficulties with Epigenetic Analysis in Neuropsychiatric Diseases
Point:
Epigenetic codes are dynamic, tissue and cell type specific
Always ask yourself whether the tissue sampled is a suitable surrogate for the affected brain cells
Access to brain tissue is difficult – use animal models.
Psychiatric studies limited to postmortem brain tissue or blood and saliva
But there is a light at the end of the tunnel: recent genome wide comparative studies have shown that there is
some correlation between changes in the blood and in the brain in terms of DNA methylation (DNA
methylome).
o This degree of correlation might be enough for us to assume that a change that has been identified in
the blood might also have occurred in the brain
o Animal models are useful here
Evidence: Aberg et al., 2013 tested two models describing how methylome-wide studies in blood are informative for
psychiatric conditions:
AIM: Investigate whether blood can be used as a proxy in methylation studies on the basis of two models
(“signature” + “mirror-site”).
Methods and Results: Methyl-binding domain enrichment and next-generation sequencing of the blood,
cortex, and hippocampus from four haloperidol-treated and ten untreated C57BL/6 mice revealed high levels
of correlation in methylation across tissues. Despite the treatment inducing a large number of methylation
changes, this correlation remains high.
CONCLUSION: Consistent with the signature model, factors that affect brain processes (i.e., haloperidol)
leave biomarker signatures in the blood and, consistent with the mirror-site model, the methylation status of
many sites in the blood mirror those in the brain.
Table of Contents
Part I: Introduction – Basic Definitions and Concepts................................................................................1
Part II: Epigenetic Mechanisms: Mechanisms of Chromatin Remodelling..................................................1
Part III: Difficulties with Epigenetic Analysis in Neuropsychiatric Diseases................................................2
Part IV: Autism Spectrum Disorders (ASD).................................................................................................3
Part V: Psychotic Disorders – PTSD, BD, and SCZ.......................................................................................4
Epigenetics of PTSD...............................................................................................................................................4
Epigenetics of Depression......................................................................................................................................9
Part VI: MeCP2 and Rett Syndrome.........................................................................................................10
Part I: Introduction – Basic Definitions and Concepts
Gene Expression
Cells use information in genes to build hundreds of different proteins, each with a unique function
Although every cell in the body contains the same DNA, they do not present with the same mRNA profiles and
do not express the same proteins
This is because gene expression is tightly regulated, so that proteins expressed in a subset of cells are
expressed in a timely manner/tissue specificity
Gene Structure
DNA is read from the 5’ to 3’ end
Promoters are key DNA regions important for the regulation of gene expression – this is where transcription of
a particular gene is initiated
o They regulate where, when and to what extent a gene is expressed
o Promoters are not active in every single cell
The 3D conformation of the DNA is important for the accessibility of TFs to the promoter region
DNA is wrapped around histones (chromatin)
Both the DNA and histones are covered with chemical tags (the epigenome)
The epigenome shapes the physical structure of the genome
o It tightly wraps inactive genes – making them unreadable (so TFs cannot bind to their promoters)
o It relaxes active genes, making them easily accessible
The epigenome is flexible – epigenetic tags react to signals from the outside world (e.g., diet, stress)
Epigenetics
Epigenetics were first described in the early 1940s by Waddington
He described epigenetic mechanisms as mechanisms necessary to understand how diverse programming of
the single genome can create different cells of multicellular organisms during development
o They “secure” the faith of a cell subtype
Epigenetic regulation is complex and dynamic, with many functions other than their role on developmental
programming
The epigenome interacts with the micro (e.g., hormones, NTs, neuronal activation/inhibition) and macro
(nutrition, drugs, pollution, etc.) environment
o Environment can influence gene expression through chromatin remodeling
This helps adaptation to the ever-changing conditions in an age and generation specific manner
Part II: Epigenetic Mechanisms: Mechanisms of Chromatin Remodelling
DNA Methylation
High degree of DNA methylation usually implies inhibition of
gene expression
The location of the methylation matters!
o Usually, DNA methylation at the promoter sequence or
upstream CpG islands correlates with the level of
expression of a gene
o The more these are methylated, the less likely the gene
will be expressed
, o Methylation at the promoter region inhibits the binding of TFs
o NB: there are other regions (e.g., enhancers) that are also important in the regulation of gene
expression
o Even though they seem far from a gene itself in a 2D structure, the 3D conformation of the DNA can
make these regions close to the actual gene
Histone Modifications
We understand very well how all the histones can be modified and their impact on gene expression
o There are a lot of possible histone modifications
o They could be on different histone proteins
o They could be on different amino acids
o They could be different modifications: phosphorylation, acetylation, methylation, ubiquitination, etc.
There are many enzymes responsible for specific modifications on specific amino acids in a
protein
Acetylation adds a -ve charge & the DNA backbone is also -vely charged, so acetylation leads to relaxation of
chromatin
These changes can be reversed – for example, HDACs (histone deacetylases remove the acetylation and
lead to the compaction of chromatin 🡪 less transcription
Different modifications have different effects on the compaction of chromatin
NB: histone modifications and DNA methylation are NOT completely independent mechanisms
o This is because when DNA is methylated, this gives the opportunity for DNA binding proteins to bind
onto methylated DNA, which can in turn recruit other proteins that can modify histones
o This happens very often
miRNA: RNA editing and RNA interference
miRNA = micro-RNA
o 18-25bp long
o They are non-coding
o More than 1000 miRNAs bind to different target mRNAs and induce RNA degradation or suppress
protein synthesis.
miRNAs are often discussed as epigenetic mechanisms because they are mechanisms of gene expression
regulation above the genome (i.e., without changing the DNA sequence)
Non-coding miRNAs are the most significant “epigenetic regulators” discovered in the last decade
They target mRNAs for degradation OR they suppress protein synthesis
o Essentially, they make sure that the targeted mRNAs are never made into a protein
Each miRNA can target hundreds of genes and each gene may be a target of several miRNAs
RNA-based mechanisms have been identified to be able to modify the higher-order structure of chromatin
Part III: Difficulties with Epigenetic Analysis in Neuropsychiatric Diseases
Point:
Epigenetic codes are dynamic, tissue and cell type specific
Always ask yourself whether the tissue sampled is a suitable surrogate for the affected brain cells
Access to brain tissue is difficult – use animal models.
Psychiatric studies limited to postmortem brain tissue or blood and saliva
But there is a light at the end of the tunnel: recent genome wide comparative studies have shown that there is
some correlation between changes in the blood and in the brain in terms of DNA methylation (DNA
methylome).
o This degree of correlation might be enough for us to assume that a change that has been identified in
the blood might also have occurred in the brain
o Animal models are useful here
Evidence: Aberg et al., 2013 tested two models describing how methylome-wide studies in blood are informative for
psychiatric conditions:
AIM: Investigate whether blood can be used as a proxy in methylation studies on the basis of two models
(“signature” + “mirror-site”).
Methods and Results: Methyl-binding domain enrichment and next-generation sequencing of the blood,
cortex, and hippocampus from four haloperidol-treated and ten untreated C57BL/6 mice revealed high levels
of correlation in methylation across tissues. Despite the treatment inducing a large number of methylation
changes, this correlation remains high.
CONCLUSION: Consistent with the signature model, factors that affect brain processes (i.e., haloperidol)
leave biomarker signatures in the blood and, consistent with the mirror-site model, the methylation status of
many sites in the blood mirror those in the brain.
