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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).

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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

Image via Wikipedia

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?

Nope.

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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