Posts Tagged ‘Epigenetics’

If you can’t sleep it’s because you’re awake in someone else’s dream.

That’s nice to know.  I’m currently being stalked by a DNA binding protein named  PAX6 that has an affinity for the H3K4me1 DNA element – which resides next to the polymorphic sites rs11208305 (chromosome 1p31) and rs718712 (chromosome 20p12) – who, themselves, are involved in the regulation of the expression of the ROR1 and PLCB1 genes, respectively.  Yeah, Freddy is sneaky like that.

These 2 SNPs were the most highly associated low-hanging fruits of a large genome association study of insomnia.  Interestingly, PAX6 is expressed both in the brain and in the pancreas (insomniacs often have high insulin levels at night).  The authors thus explored the notion that the expression of ROR1 and PLCB1 might be regulated by PAX6 both in the brain (where it can influence neural and circadian functions) AND in also the pancreas (where it can influence insulin secretion).


Caveat:  The authors report a minor allele frequency of 0.03353 for the “C” allele at rs11208305.  Such rare alleles can vary in frequency dramatically across populations and lead to false positive results in case-control analyses.

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Check it out!

October 30 – November 1, 2011, The Westin Boston Waterfront, Boston, MA, USA

The field of epigenetics has come to the fore in recent years, making its mark in both basic research and also fields relevant to human disease, such as stem cells and cancer. “Epigenetics” has become synonymous with modifications to DNA and associated molecules that influence whether genes are on or off. But are these epigenetic modifications self-propagating and inherited like DNA, the physical manifestation of Mendel’s gene? Given the great interest in the topic and huge public and private investment made in epigenetics, Cell Press has decided to tackle this and other aspects of epigenetics in a multi-day meeting. In addition to fostering critical discussions on the proposed mechanisms of epigenetic inheritance and the challenges that lay ahead in understanding these mechanisms, the meeting will focus on more well established epigenetic mechanisms and how they are implemented in cell and developmental biology, particularly the maintenance of cell states, such as occurs during X-inactivation and polycomb-mediated gene silencing. The scope will be broad, giving the interested attendee a glimpse of epigenetics at both the molecular as well as the organism level.

As the field of epigenetics gains momentum, this is the perfect time to take a breather, stand back, and take a critical look at the claims, the issues to be addressed, and how we move ahead.

Topic List:
– Transgenerational Epigenetic Inheritance
– Inheritance of cellular states: x-inactivation, imprinting, and lambda phage
– Replication of chromatin
– RNA and epigenetic inheritance
– Mechanisms of polycomb-mediated gene silencing

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THE ultimate guide to your genome … ‘nuf said.

The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.


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Methylation Sites on DNA

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DNA methylation is THE key driver of epigenetic regulationWhere goest CpG methylation, then followest chromatin remodellingNOT the other way around.

“The heritability of genomic methylation patterns clearly shows that once established, DNA methylation is dominant over chromatin modifications.”

Some neurodevelopmental processes (here) seem to depend on DNA methylation, but, is this the main purpose of all this methylation?


Our genome is a huge junk pile.  That’s right … we are built from a genome, of which some 40%, are old retroviruses, transposons and other broken legacies of foreign DNA that inserted themselves into the genomes of our mammalian ancestors.  These ancient viruses can be very dangerous and wreak havoc if they are allowed to be transcribed.  DNA methylation helps keep this from happening.  Its a HUGE job … some 60% of all CpG’s are methylated … likely THE main purpose of DNA methylation.

“The lack of cell-type-specific methylation at either enhancers or promoters indicates that DNA methylation is likely to have a negligible or very small role in development, and that the methylation changes seen at some low-CpG promoters are likely to be a result of transcriptional activation rather than a cause.”

“The data indicate that the bulk of the genome is methylated as the default state, and unmethylated regions are protected from a promiscuous DNA methylating system by a combination of very high CpG densities and histone modifications and variants that repel DNA methyltransferase complexes.”

So, we must keep in mind when reading the epigenetic literature (a methyl group here or there contributes to less anxiety) that there is a much more vital process happening (ie., lack of a methyl group here or there can lead to a lethal viral attack). Occasionally, in the process of keeping us alive, our physiological systems can make life difficult.  C’est la vie!

Also, it appears that methylation is like an enormous fire-hose spraying methyl groups everywhere in the genome to dampen the ground and prevent any small fires (viruses) from igniting. How much stock can you put in research findings that hinge on the appearance/disappearance of 1 or 2 errant methyl groups?

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Can you imagine uttering that phrase in the future? Yep.

“… transgenic mice with increased Setdb1 expression in adult forebrain neurons show antidepressant-like phenotypes in behavioral paradigms for anhedonia, despair and learned helplessness.”

SETDB1 is a protein that helps methylate lysine #9 on the histone H3 DNA binding protein … which leads to DNA CpG methylation … which leads to repression of the NMDA receptor subunit, NR2B/Grin2b … which leads to the anti-depressant-like phenotype.

Recall that 60% of CpGs are methylated and that, in the brain (unlike other terminally differentiated tissues), these methyl groups are popping on and off a lot … perhaps reflecting an ongoing, constant tuning of the inhibition/excitation balance.

thanks for the pic whaddap.

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“Listen Eric, you should think about how useful your newfangled Personal Genome is going to be.  There are a lot of reasons why all this information doesn’t tell you much”

“For example, have you thought about epigenetic effects that might be environmentally induced and can be transmitted across multiple subsequent generations?  Genotypes of individuals in previous generations might even be a better predictor of phenotype than an individual’s own genotype.”

“I know that Copy-Number Polymorphic (CNP) duplications are highly variable among individual and are considered inaccessible by most existing genotyping and sequencing technologies, but I’m still getting my genome sequenced anyway.”

“Can you please help Eric understand that rare variants and large variants (deletions, duplications and inversions) are individually rare, but collectively common in the human population might account for much more of heritability than common variation.  Nothing is known about these rare variants!”

“Yeah, Eric doesn’t realize that a very large number of closely linked genes can exhibit context-dependent and non-additive effects.”

“Gene by environment innnterraaaaactiiooon … coooool.”

–real science here.

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NYCSub 7 car exterior
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Playa with gold NY Yankees hat worn sideways:  Man, I’ve got mad feva for the flava of these chips.

Hipster girl with multicolor wool sherpa hat:  You better watch out playa, you’ll pass on some ill health to your kids.

Playa:  Kids! I ain’t tryin’ to have no kids.  Besides, that’s some Lamarckian shit you’re talkin’.  Dads can’t pass on stuff they get from eatin’ junk food … only girls can.

Girl:  You ever hear of epigenetic reprogramming?

Playa:  You buggin’ gurrrl.  How are my sperm cells supposed to carry all that “past history” and shit to my kids.  I mean the fucked up cheeto-eating fat cells are in my ass, not my balls.  My sperm cells ain’t got nuthin’ but some nekkid DNA coiled up in them – no room for the epigenome in MY sperm babe.  Did I say my DNA was naaaked?

Girl:  You’re balls ain’t as dumb as you think.

Playa:  Oooh Shit!  Say that again!  Please!  Tell me about my sperm cells too!

Girl:  Slow down playa.  Read the paper by Carone et al., “Paternally Induced Transgenerational Environmental Reprogramming of Metabolic Gene Expression in Mammals” [DOI 10.1016/j.cell.2010.12.008].  They show that mouse fathers can pass on all kinds of crazy changes to their offspring’s liver function depending on the dad’s diet.

Playa:  Damn!  So I have to think about what I’m eating now? what I’m puttin’ into my sperm cells?

Girl:  If you want your nekkid DNA to be with me … ha ha!

Playa: Shit, that re-programming shit is messed UP!

Girl:  Don’t hate the playa, just hate the game – the epigenetic game!

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Myelin Repair Foundation Logo
Image by Myelin Repair Foundation via Flickr

from Ye et al., 2009:

HDAC1/2 genes encode proteins that modify the epigenome (make it less accessible for gene expression).

When HDAC1/2 functions around the HES5 and ID2/4 (repressors of white matter development) genes, the epigenetic changes (less acetylation of chromatin) helps to repress the repressors.

This type of epigenetic repression of gene expression (genes that repress white matter development) is essential for white matter development.

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remember a day before today
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Most cells in your adult body are “terminally differentiated” – meaning that they have developed from stem cells into the final liver, or heart, or muscle or endothelial cell that they were meant to be.  From that point onward, cells are able to “remember” to stay in this final state – in part – via stable patterns of DNA methylation that reinforce the regulation of “the end state” of gene expression for that cell.  As evidence for this role of DNA methylation, it has been observed that levels of DNA methyl transferase (DNMT) decline when cells are fully differentiated and thus, cannot modify or disrupt their patterns of methylation.

NOT the case in the brain! Even though neurons in the adult brain are fully differentiated, levels of methyl transferases – DO NOT decline.  Why not? Afterall, we wouldn’t want our neurons to turn into liver cells, or big toe cells, would we?

One hypothesis, suggested by David Sweatt and colleagues is that neurons have more important things to “remember”.   They suggest in their fee and open research article, “Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus” [doi: 10.1074/jbc.M511767200] that:

DNA methylation could have lasting effects on neuronal gene expression and overall functional state. We hypothesize that direct modification of DNA, in the form of DNA (cytosine-5) methylation, is another epigenetic mechanism for long term information storage in the nervous system.

By measuring methylated vs. unmethylated DNA in the promoter of the reelin and BDNF genes and relating this to electrophysiological measures of synaptic plasticity, the research team finds correlations between methylation status and synaptic plasticity.  More specifically, they find that zebularine (an inhibitor of DNMT) CAN block long-term potentiation (LTP), but NOT block baseline synaptic transmission nor the ability of synapses to fire in a theta-burst pattern (needed to induce LTP).

This suggests that the epigenetic machinery used for DNA methylation may have a role in the formation of cellular memory – but not in the same sense as in other cells in the body – where cells remember to remain in a terminally differentiated state.

In the brain, this epigenetic machinery may help cells remember stuff that’s more germane to brain function … you know … our memories and stuff.

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The human brain has some 100 billion neurons.  That sounds like a lot, but I’m still keen on keeping ALL of mine healthy and in good working order.  One way that cells protect themselves from damage and untimely death is by protecting their DNA – by wrapping it up and coiling it tightly – using chromatin proteins – which keeps it away from chemical and viral damage.  This is especially important in the brain, since – unlike the skin or gut – we can’t really re-grow brain tissue once its damaged.  We have to protect the neurons we have!

Here’s the problem. In order to USE the BRAIN (to learn and remember stuff) we have to also USE the GENOME (to encode the proteins that synapses use in the process of memory formation).  When we’re thinking, we have to take our precious DNA out of its protective supercoiled, proteinaceous shell and allow the double helix to melt into single strands and expose their naked A’s, G’s, T’s and C’s to the chemical milieu (to the start the transcription process).  This is risky business damage to DNA can lead to cell death!

One might imaging that its best to carry out this precarious act quickly and in proximity to DNA repair enzymes (I’d think).  A very important job that includes: uncoiling chromatin superstructures, transcribing DNA (that encodes proteinaceous building blocks that synapses use to strengthen and weaken themselves) – and then – making sure there was no damage incurred along the way.  A BIG job that MUST get done each and every time my cells engage in learning.  Wow!  I didn’t realize that learning new stuff means I’m exposing my DNA to damage?  Hmm … I wonder if that PhD was worth it?

To perform this important job, it seems there is an amazing handyman of a molecule named poly(ADP-ribose) polymerase-1 (PARP-1).  Amazing, because it – itself – can function in many of the steps involved in uncoiling chromatin structures, transcription initiation and DNA repair.  The protein that can “do it all” … get the job done quickly and even fix any errors made along the way! It is known to function in the so-called base excision repair (BER) pathway and is also known have a role in transcription through remodeling of chromatin by ADP-ribosylating histones and relaxing chromatin structure, thus allowing transcription to occur (click here for a great open review of PARP-1).  Nice!

According to OMIM, earlier studies by Cohen-Armon et al. (2004) found that poly(ADP-ribose) polymerase-1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because poly(ADP-ribosyl)ation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells (indeed, PARP-1 knock-out mice are more sensitive to DNA damage), it was surprising that activation of the polymerase occurred during learning and was required for long-term memory. Cohen-Armon et al. (2004) suggested that the fast and transient decondensation of chromatin structure by poly(ADP-ribosyl)ation enables the transcription needed to form long-term memory without strand breaks in DNA.

A recent article in Journal of Neuroscience seems to confirm this function –  now in the mouse brain.  Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation [doi:10.1523/JNEUROSCI.3010-10.2010] by Fontán-Lozano et al., examined cells in the hippocampus at different times during the learning of an object recognition paradigm.  They confirm (using a PARP-1 antagonist) that PARP-1 is needed to establish object memory and also that PARP-1 seems to contribute during the paradigm and up to 2 hours after the training session.  They suggest that the poly(ADP-ribosyl)ation of histone H1 influences whether H1 is bound or unbound and thus helps regulate the opening and closing of the chromatin so that transcription can take place. 

Nice to know that PARP-1 is on the job!  Still am wondering if the PhD was worth all the learning.  Are there trade-offs at play here?  MORE learning vs. LESS something?   Perhaps. Check out the paper by Grube and Bürkle (1992) – Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. This gene may influence life span!

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Cinematicode wall
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As far as science movies go, the new movie, “To Age or Not To Age” seems like a lot of fun.  The interview with Dr. Leonard Guarente suggests that the sirtuin genes play a starring role in the film.  Certainly,  an NAD+ dependent histone deacetylase – makes for a sexy movie star – especially when it is able to sense diet and metabolism and establish the overall lifespan of an organism.

One comment in the movie trailer, by Aubrey de Grey, suggests that humans may someday be able to push the physiology of aging to extreme ends.  That studies of transgenic mice over-expressing SIRT1 showed physiological properties of calorie-restricted (long lived) mice – even when fed ad libitum – suggests that something similar might be possible in humans.

Pop a pill and live it up at your local Denny’s for the next 100 years?  Sounds nice (& a lot like grad school).

Just a few twists to the plot here.  It turns out that – in the brain – SIRT1 may not function as it does in the body.  Here’s a quote from a research article “Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restriction” that inactivated SIRT1 just in the brain:

Our findings suggest that CR triggers a reduction in Sirt1 activity in hypothalamic neurons governing somatotropic signaling to lower this axis, in contrast with the activation of Sirt1 by CR in many other tissues. Sirt1 may have evolved to positively regulate the somatotropic axis, as it does insulin production in β cells, to control mammalian health span and life span in an overarching way. However, the fact that Sirt1 is a positive regulator of the somatotropic axis may complicate attempts to increase murine life span by whole-body activation of this sirtuin.

To a limited extent, it seems that – in the brain – SIRT1 has the normal function of promoting aging.  Therefore, developing “pills” that are activators of SIRT1 would be good for the body, but somehow might be counteracted by what the brain would do.  Who’s in charge anyway?  Mother Nature will not make it easy to cheat her! Another paper published recently also examined the role of SIRT1 in the brain and found that – normally – SIRT1 enhances neuronal plasticity (by blocking the expression of a  micro-RNA miR-134 that binds to the mRNA of, and inhibits the translation of, synaptic plasticity proteins such as CREB).

So, I won’t be first to line up for SIRT1 “activator” pills (such as Resveratrol), but I might pop a few if I’m trying to learn something new.

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Mother Nature
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The current buzz about about GWAS  and longevity and GWAS in general has stirred up many longstanding inconvenient issues that arise when trying to interpret the results of very large, expensive and worthwhile genetic studies.  Its seems that Mother Nature does not give up her secrets without a fight.

One of the most common “inconvenient issues” is the fact that so many of the SNPs that come out of these studies are located far away from protein-encoding exons.  This ubiquitous observation is almost always followed with, “well, maybe its in linkage disequilibrium with a more functional SNP” or something along these lines – wherein the authors get an automatic pass.  OK by me.

Another “inconvenient issue” is the fact that many of these SNPs are of minimal effect and don’t exactly add up or interact to account for the expected heritability.  This problem of “missing heritability” is a big one (see some new insights in the latest issue of Nature Genetics) leading many to suspect that the effects of genes are dependent on complex interactions with each other and the environment.

A recent paper, “A map of open chromatin in human pancreatic islets” [doi:10.1038/ng.530] by Gaulton and colleagues caught my eye because it seems to shed light on both of these particular inconvenient issues.  The authors find that the diabetes risk variant rs7903146 in the TCF7L2 gene is both located in an intron and subject to epigenetic regulation (our sedentary, high-fat, high-stress lives can potentially interact with the genome by causing epigenetic change).

It appears that the T-allele of the intronic rs7903146 is correlated with a more open, transcription-prone form of DNA/chromatin than is the C-allele. The authors confirmed this using both chromatin mapping and gene expression assays on pancreatic islet cells harvested from non-diabetic donors and islet cell-lines.  The results suggest that the risk-conferring T-allele of this intronic SNP may be driving expression (gain-of-function) of the TCF7L2 gene.  What types of environmental stimuli might also impact the opening and closing of chromatin at this location?

This type of interplay of environment, genome and epigenome is probably rampant in the area of brain and behavior – so perhaps the study of diabetes will provide some clues to the many GWAS SNPs that are far away from exons. More on the genetics of epigenetics here.

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Nucleosome structure.
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pointer to the NOVA program on epigenetics “Ghost in Your Genes” (YouTube link here).  Fantastic footage.  Great intro to epigenetics and so-called trans-generational effects and the inheritance of epigenetic marks – which, in some cases – are left by adverse or stressful experience.  A weird, wild, game-changing concept indeed – that my grandchildren could inherit epigenetic changes induced in my genome by adverse experience.

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Where's Waldo in Google Maps?
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In an earlier post on Williams Syndrome, we delved into the notion that sometimes a genetic variant can lead to enhanced function – such as certain social behaviors in the case of WS.  A mechanism that is thought to underlie this phenomenon has to do with the way in which information processing in the brain is widely distributed and that sometimes a gene variant can impact one processing pathway, while leaving another pathway intact, or even upregulated.  In the case of Williams Syndrome a relatively intact ventral stream (“what”) processing but disrupted dorsal stream (“where”) processing leads to weaker projections to the frontal cortex and amygdala which may facilitate gregarious and prosocial (a lack of fear and inhibition) behavior.  Other developmental disabilities may differentially disrupt these 2 visual information processing pathways.  For instance, developmental dyspraxia contrasts with WS as it differentially disrupts the ventral stream processing pathway.

A recent paper by Woodcock and colleagues in their article, “Dorsal and ventral stream mediated visual processing in genetic subtypes of Prader–Willi syndrome” [doi:10.1016/j.neuropsychologia.2008.09.019] ask how another developmental disability – Prader-Willi syndrome – might differentially influence the development of these information processing pathways.  PWS arises from the lack of expression (via deletion or uniparental disomy) of a cluster of paternally expressed genes in the 15q11-13 region (normally the gene on the maternally inherited chromosome is silent, or imprintedrelated post here).  By comparing PWS children to matched controls, the team reports evidence showing that PWS children who carry the deletion are slightly more impaired in a task that depends on the dorsal “where” pathway whilst some sparing or relative strength in the ventral “what” pathway.

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Last year I dug a bit into the area of epigenetics (indexed here) and learned that the methylation (CH3) and acetylation (OCCH3) of genomic DNA & histones, respectively, can have dramatic effects on the structure of DNA and its accessibility to transcription factors – and hence – gene expression.  Many of the papers I covered suggested that the environment can influence the degree to which these so-called “epigenetic marks” are covalently bonded onto the genome during early development.  Thus, the thinking goes, the early environment can modulate gene expression in ways that are long-lasting – even transgenerational.  The idea is a powerful one to be sure.  And a scary one as well, as parents who read this literature, may fret that their children (and grandchildren) can be epigenetically scarred by early nutritional, physical and/or psycho-social stress.  I must admit that, as a parent of young children myself, I began to wonder if I might be negatively influencing the epigenome of my children.

I’m wondering how much physical and/or social stress is enough to cause changes in the epigenome?  Does the concern about epigenetics only apply to exposure to severe stress?  or run of the mill forms of stress?  How much do we know about this?

This year, I hope to explore this line of inquiry further.  For starters, I came across a fantastic paper by Fraga et al., entitled, “Epigenetic differences arise during the lifetime of monozygotic twins” [doi:10.1073/pnas.0500398102].   The group carries out a remarkably straightforward and time honored approach – a twin study – to ask how much identical twins differ at the epigenetic level.  Since identical twins have the same genome sequence, any differences in their physiology, behavior etc. are, strictly speaking, due to the way in which the environment (from the uterus to adulthood) shapes their development.  Hence, the team of Fraga et al., can compare the amount and location of methyl (CH3) and acetyl (OCCH3) groups to see whether the environment has differentially shaped the epigenome.

An analysis of some 40 identical twin pairs from ages 3-74 years old showed that – YES – the environment, over time, does seem to shape the epigenome (in this case of lymphocytes).  The most compelling evidence for me was seen in Figure 4 where the team used a method known as Restriction Landmark Genomic Scanning (RLGS) to compare patterns of methylation in a genome-wide manner.  Using this analysis, the team found that older twin pairs had about 2.5 times as many differences as did the epigenomes of the youngest twin pairs.  These methylation differences also correlated with gene expression differences (older pairs also had more gene expression differences) and they found that the individual who showed the lowest levels of methylation also had the highest levels of gene expression.  Furthermore, the team finds that twin pairs who lived apart and had more differences in life history were more likely to have epigenetic differences.  Finally, measures of histone acetylation seemed consistent with the gradient of epigenetic change over time and life-history distance.

Thus it seems that, as everyday life progresses, the epigenome changes too.  So, perhaps, one does not need extreme forms of stress to leave long-lasting epigenetic marks on the genome?  Is this true during early life (where the team did not see many differences between pairs)?  and in the brain (the team focused mainly on lymphocytes)?  Are the differences between twins due to the creation of new environmentally-mediated marks or the faulty passage of existing marks from dividing cell-to-cell over time?  Will be fun to seek out information on this.

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Some quick sketches that might help put the fast-growing epigenetics and cognitive development literature into context.  Visit the University of Utah’s Epigenetics training site for more background!

The genome is just the A,G,T,C bases that encode proteins and other mRNA molecules.  The “epi”genome are various modification to the DNA – such as methylation (at C residues) – and acetylation of histone proteins.   These changes help the DNA form various secondary and tertiary structures that can facilitate or block the interaction of DNA with the transcriptional machinery.

When DNA is highly methylated, it generally is less accessible for transcription and hence gene expression is reduced.  When histone proteins (purple blobs that help DNA coil into a compact shape) are acetylated, the DNA is much more accessible and gene expression goes up.

We know that proper epigenetic regulation is critical for cognitive development because mutations in MeCP2 – a protein that binds to methylated C residues – leads to Rett syndrome.  MeCP2 is normally responsible for binding to methylated DNA and recruiting histone de-acetylases (HDACs) to help DNA coil and condense into a closed form that is inaccessible for gene expression (related post here).

When DNA is accessible for gene expression, then it appears that – during brain development – there are relatively more synaptic spines produced (related post here).  Is this a good thing? Rett syndrome would suggest that – NO – too many synaptic spines and too much excitatory activity during brain development may not be optimal.  Neither is too little excitatory (too much inhibitory) activity and too few synaptic spines.  It is likely that you need just the right balance (related post here). Some have argued (here) that autism & schizophrenia are consequences of too many & too few synapses during development.

The sketch above illustrates a theoretical conjecture – not a scenario that has been verified by extensive scientific study. It tries to explain why epigenetic effects can, in practice, be difficult to disentangle from true (changes in the A,G,T,C sequence) genetic effects.  This is because – for one reason – a mother’s experience (extreme stress, malnutrition, chemical toxins) can – based on some evidence – exert an effect on the methylation of her child’s genome.  Keep in mind, that methylation is normal and widespread throughout the genome during development.  However, in this scenario, if the daughter’s behavior or physiology were to be influenced by such methylation, then she could, in theory, when reaching reproductive age, expose her developing child to an environment that leads to altered methylation (shown here of the grandaughter’s genome).  Thus, an epigenetic change would look much like there is a genetic variant being passed from one generation to the next, but such a genetic variant need not exist (related post here, here) – as its an epigenetic phenomenon.  Genes such as BDNF have been the focus of many genetic/epigenetic studies (here, here) – however, much, much more work remains to determine and understand just how much stress/malnutrition/toxin exposure is enough to cause such multi-generational effects.  Disentangling the interaction of genetics with the environment (and its influence on the epigenome) is a complex task, and it is very difficult to prove the conjecture/model above, so be sure to read the literature and popular press on these topics carefully.

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We are all familiar with the notion that genes are NOT destiny and that the development of an individual’s mind and body occur in a manner that is sensitive to the environment (e.g. children who eat lots of healthy food grow bigger and stronger than those who have little or no access to food).  In the case of the brain, one of the ways in which the environment gets factored into development – is via so-called “sensitive periods” where certain parts of the brain transiently rely on sensory experience in order to develop.  Children born with cataracts, for example, will have much better vision if the cataracts are removed in the first few weeks of life rather than later on.  This is because the human visual system has a “sensitive period” early in development where it is extra-sensitive to visual input and, after which, the function and connectivity of various parts of the system is – somewhat permanently – established for the rest of the person’s life.  Hence, if there is little visual input (cataracts) during the sensitive period, then the visual system is somewhat permanently unable to process visual information – even if the cataracts are subsequently removed.  (To learn more about this topic, visit Pawan Sinha’s lab at M.I.T and his Project Prakash intervention study on childhood blindness.)

What the heck is an “in”sensitive period then?   Well, whereas visual input is clearly a “good thing” for the sensitive period of visual development, perhaps some inputs are “bad” and it may be useful to shield or protect the brain from exposure.  Maybe some environmental inputs are “bad” and one would not want the developing brain to be exposed to them and say, “OK, this (bad stuff) is normal“.  As a parent, I am constantly telling my children that the traffic-filled street is a “bad place” and, like all parents, I would not want my children to think that it was OK to wander into the street.  Clearly, I want my child to recognize the car-filled street as a “bad thing”.

In the developing brain, it turns out that there are some “bad things” that one would NOT like (the brain) to get accustomed to.  Long-term exposure to glucocorticoids is one example – well-known to cause a type of neuronal remodelling in the hippocampus, that is associated with poor cognitive performance (visit Bruce McEwen’s lab at Rockefeller University to learn more about this).  Perhaps an “in”sensitive period – where the brain is insensitive to glucocorticoids – is one way to teach the brain that glucocorticoids are “bad” and DO NOT get too familiar with them (such a period does actually occur during early post-natal mammalian development).  Of course, we do need our brains to mount an acute stress response, if and when, we are being threatened, but it is also very important that the brain learn to TURN-OFF the acute stress response when the threat has passed – an extensive literature on the deleterious effects of chronic exposure to stress bears this out.  Hence, the brain needs to learn to recognize the flow of glucocorticoids as something that needs to be shut down.

OK, so our developing brain needs to learn what/who is “good vs. bad”.  Perhaps sensitive and insensitive periods help to reinforce this learning – and also – to cement learning into the system in a sort of permanent way (I’m really not sure if this is the consensus view, but I’ll try and podcast interview some of the experts here asap).  In any case, in the case of the visual system, it is clear that the lack of visual input during the sensitive period has long lasting consequences.  In the case of the stress response, it is also clear that if there is untoward stress early in development, one can be (somewhat) destined to endure a lifetime of emotional difficulty.  Previous posts here, here, here cover research on behavioral/genomic correlates of early life stress.

Genes meet environment in the epigenome during sensitive and insensitive periods?

As stated at the outset – genes are not destiny.  The DNA cannot encode a system that knows who/what is good vs. bad, but rather can only encode a system of molecular parts that can assemble to learn these contingencies on the fly.  During sensitive periods in the visual system, cells in the visual system are more active and fire more profusely during the sensitive period. This extra firing leads to changes in gene expression in ways that (somewhat) permanently set the connectivity, strength and sensitivity of visual synapses.  The expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections are well-known tagets of activity-induced gene expression.  Hence the environment “interacts” with the genome via neuronal firing which induces gene expression which – in turn – feeds back and modulates neuronal firing.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Similarly, in the stress response system, the environment induces changes in the firing of cells in the hypothalamus which leads (through a series of intermediates) to the release of glucocorticoids.  Genes induced during the firing of hypothalamic cells and by the release of glucocorticoid can modify the organism’s subsequent response to stressful events.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Digging deeper into the mechanism by which neuronal firing induces gene expression, we find an interesting twist.   Certainly there is a well-studied mechanism wherein neuronal firing causes Ca++ release which activates gene expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections – for many decades.  There is another mechanism that can permanently mark certain genes and alter their levels of expression – in a long-lasting manner.  These are so-called epigenetic mechanisms such as DNA methylation and acetylation.  As covered here and here, for instance, Michael Meaney’s lab has shown that DNA CpG methylation of various genes can vary in response to early-life stress and/or maternal care. In some cases, females who were poorly cared for, may, in turn, be rather lousy mothers themselves as a consequence of these epigenetic markings.

A new research article, “Dynamic DNA methylation programs persistent adverse effects of early-life stress” by Chris Murgatroyd and colleagues [doi:10.1038/nn.2436] explores these mechanisms in great detail.  The team explored the expression of the arginine vasopressin (AVP) peptide – a gene which is important for healthy social interaction and social-stress responsivity.  Among many other interesting results, the team reports that early life stress (using a mouse model) leads to lower levels of methylation in the 3rd CpG island which is located downstream in a distal gene-expression-enhancer region.  In short, more early-life stress was correlated with less methylation, more AVP expression which is known to potentiate the release of glucocorticoids (a bad thing).   The team reports that the methyl binding MeCP2 protein, encoded by the gene that underlies Rett syndrome, acts as a repressor of AVP expression – which would normally be a good thing since it would keep AVP levels (and hence glucocorticoid levels) down.  But unfortunately, early-life stress removes the very methyl groups to which MeCP2 binds and also the team reports that parvocelluar neuronal depolarization leads to phosphorylation (on serine residue #438) of MeCP2 – a form of MeCP2 that is less accessible to its targets.  So, in  a manner similar to other examples, early life stress can have long-lasting effects on gene expression via an epigenetic mechanism – and disables an otherwise protective mechanism that would shield the organism from the effects of stress.  Much like in the case of Rett syndrome (as covered here) it seems that when MeCP2 is bound – then it silences gene expression – which would seem to be a good thing when it comes to the case of AVP.

So who puts these epigenetic marks on chromosomes and why?

I’ll try and explore this further in the weeks ahead.  One intriguing idea about why methylation has been co-opted among mammals, has to do with the idea of parent-offspring conflict.  According to David Haig, one of the experts on this topic, males have various incentives to cause their offspring to be large and fast growing, while females have incentive to combat the genomic tricks that males use, and to keep their offspring smaller and more manageable in size.  The literature clearly show that genes that are marked or methylated by fathers (paternally imprinted genes) tend to be growth promoting genes and that maternally imprinted genes tend to be growth inhibitors.  One might imagine that maternally methylated genes might have an impact on maternal care as well.

Lastly, the growth promoting/inhibiting effects of paternal/maternal genes and gene markings is now starting to be discussed somewhat in the context of autism/schizophrenia which have have been associated with synaptic under-/over-growth, respectively.

Building a brain is already tough enough – but to have to do it amidst an eons-old battle between maternal and paternal genomes.  Sheesh!  More on this to come.

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Gravestone of Samuel Coleridge-Taylor,Wallington
Image by sludgegulper via Flickr

Few events are as hard to understand as the loss of a loved one to suicide – a fatal confluence of factors that are oft scrutinized – but whose analysis can provide little comfort to family and friends.  To me, one frightening and vexing aspect of what is known about the biological roots of depression, anxiety, impulsivity and other mental traits and states associated with suicide, is the way in which early life (even prenatal) experience can influence events in later life.  As covered in this blog here and here, there appear to be very early interactions between emotional experience in early life and the methylation of specific points in the genome.  Such methylation – often referred to as epigenetic marks – can regulate the expression of genes that are important for synaptic plasticity and cognitive development.

The recent paper, “Alternative Splicing, Methylation State, and Expression Profile of Tropomyosin-Related Kinase B in the Frontal Cortex of Suicide Completers” is a recent example of a link between epigenetic marks and suicide.  The team of Ernst et al., examined gene expression profiles from the frontal cortex and cerebellum of 28 males lost to suicide and 11 control, ethnically-matched control participants.  Using a subject-by-subject comparison method described as “extreme value analysis” the team identified 2 Affymetrix probes: 221794_at and 221796_at – that are specific to NTRK2 (TRKB) gene – that showed significantly lower expression in several areas of the frontal cortex.  The team also found that these probes were specific to exon 16 – which is expressed only in the TRKB.T1 isoform that is expressed only in astrocytes.

Further analysis showed that there were no genetic differences in the promoter region of this gene that would explain the expression differences, but, however, that there were 2 methylation sites (epigenetic differences) whose methylation status correlated with expression levels (P=0.01 and 0.004).  As a control, the DNA-methylation at these sites was not correlated with TRKB.T1 expression when DNA and RNA was taken from the cerebellum (a control since the cerebellum is not thought to be directly involved in the regulation of mood).

In the case of TRKB.T1 expression, the team reports that more methylation at these 2 sites in the promoter region is associated with less TRKB.T1 expression in the frontal cortex.  Where and when are these marks laid down?  Are they reversible?  How can we know or suspect what is happening to our epigenome (you can’t measure this by spitting into a cup as with current genome sequencing methods)? To me, the team has identified an important clue from which such follow-up questions can be addressed.  Now that they have a biomarker, they can help us begin to better understand our complex and often difficult emotional lives within a broader biological context.

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creb1According to Joseph LeDoux, “One of the most important contributions of modern neuroscience has been to show that the nature/nurture debate operates around a false dichotomy: the assumption that biology, on one hand, and lived experience, on the other, affect us in fundamentally different ways” (ref).  Indeed.  While I know not where the current debate stands, I’d like to point to a fantastic example of just how inextricably linked the genome is to the environment.  In their recent paper, “A Biological Function for the Neuronal Activity-Dependent Component of Bdnf Transcription in the Development of Cortical Inhibition” [doi:10.1016/j.neuron.2008.09.024]  Hong et al., ask what happens when you take away the ability of a given gene to respond to the environment.  This is not a traditional “knockout” experiment – where the gene is inactivated from the moment of conception onwards – but rather a much more subtle type of experimental manipulation.  What happens when you prevent nurture from exerting an effect on gene expression?

The team focused on the BDNF gene whose transcription can be initiated from any one of eight promoter sites (I-XIII).  These sites vary in activity depending on the phase of development and/or the tissue or type of cell – all of which make for a complex set of instructions able to turn the BDNF gene on and off in precise developmental and/or tissue-specific ways.  In the case of promoter IV, it appears to be triggered in the cortex in response to Ca++ release that occurs when neurons are firing – a phenomena called, “neuronal activity dependent transcription” – a top example of how the environment can influence gene expression.  Seeing as how BDNF promoter IV is important for this type of environment-induced gene expression, the team asked what happens when you remove this particular promoter?

To do this, the team constructed – keep in mind that these are – mice that contain mutations in several of the Calcium (Ca++) response elements in the promoter IV region.  They introduced point mutations so that the Ca++ sensitive protein CREB could not bind to the promoter and activate gene expression.  OK, so what happens?

Firstly, the team reports that the mutant mice are more or less indistinguishable from controls in appearance, gait, growth rate, brain size and can also reproduce and transmit the mutations.  WOW! Is that one strike AGAINST nurture? The team then shows that BDNF levels are more than 50% reduced in cultured neurons, but that levels of other immediate early genes are NOT affected (as expected).  In living animals, the effects were similar when they asked how much gene expression occurs in the sensory cortex when animals are exposed to light (after an extended period of darkness).  OK, so there are few effects, so far, other than lower levels of nurture-induced BDNF expression – hmmm. Looking more closely however, the team found that the mutant mice generated lower levels of inhibitory neuron activity – as measured by the firing of miniature inhibitory postsynaptic currents.  Follow-on results showed that the total number of inhibitory neurons (parvalbumin and NPY + GABAergic cells) was no different than controls and so it would seem that the activity dependence of BDNF is important for the maintenance of inhibitory synapses.

Hence, the team has found that what “nurture” does (via the BDNF promoter IV in this case) is to exert an effect on the connectivity of inhibitory neurons.  Wow, thanks mother nurture!  Although it may seem like an obscure role for something as important as THE environment, the team points out that the relative balance of excitation-to-inhibition (yin-yang as covered here for Rett syndrome) is crucial for proper cognitive development.

To explore the notion of inhibory/excitation balance further, check out this (TED link) video lecture, where Michael Merzenich describes this imbalance as a “signal-to-noise” problem wherein some children’s brains are rather noisy (due to any number of genetic/environmental reasons – such as, perhaps, poorly maintained inhibitory connections).  This can make it harder to develop and function in life.  Perhaps someday, the genetic/environment research like that of Hong and colleagues will inform the rehabilitative strategies developed by Merzenich.

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