Wednesday, January 16, 2013

Epigenetics -- what else don't we know?

Epigenetics -- a hot topic
Epigenetics* is a buzzword these days, in genetics, yes, but it is appealing enough that it is trending in general usage as well. For better or worse.  While the idea that factors other than changes in DNA can affect development was hypothesized almost a century ago, and called epigenesis by CH Waddington, epigenetics is now more often considered to be changes in the genome that don't involve changes in DNA sequence. Generally this involves chemical modification of nucleotides that causes a gene to be silenced, and many instances have been documented, pathological and not.

Epigenetic mechanisms. Source: Wikimedia Commons
But, much as, say, political scientists invoke genetics to explain why we vote the way we do, or economists to explain our economic behavior, people are invoking epigenetics to explain things like the 'culture of poverty' (due to epigenetic changes because of maternal malnutrition during pregnancy), or psychiatric diseases that seem to be genetic but for which genes have not been identified, or even homosexuality (due to epigenetic signaling that is usually beneficial to the parent, but can be transferred to a fetus of the opposite sex, affecting subsequent sexual behavior). 

Epigenetics is appealing because it's not strict genetic reductionism, and finding genes 'for' traits, particularly behaviors, has proven to be frustratingly difficult (well, at least when done properly), and yet epigenetics explains traits in terms of tractable biological markers, such as methylation of mRNA or histone modification. Whether epigenetics is always correctly applied is another matter.

Epigenetics documented
But the actual, documentable science of epigenetics marches on.  A paper in the Dec 14 issue of Science ("Epigenetic Regulation by Long Noncoding RNAs," Lee) adds a new twist to the epigenetic story, addressing long noncoding RNAs and asks about their function.  Thousands of lncRNAs have been found in the last five years, and their function is just beginning to be documented.

The ENCODE project has shown that 70-90% of the mammalian genome is transcribed, yielding a very large 'transcriptome' of long (defined as greater than 100 nucleotides) noncoding RNA (lncRNA), and that this 'pervasive transcription' actually happens seems to be emerging as the consensus view (though, see this post on differences of opinion on this).

ENCODE, again, has shown that there are about 10 "isoforms overlapping any previously annotated genes, thereby challenging the traditional definition of a gene."  That is, whereas the classic view of messenger RNA is that it is transcribed from coding regions within protein-coding genes -- which comprise only about 1% of the genome -- now it seems that most of the non-coding genome is also transcribed, and that the transcripts start and stop in unexpected places, given accepted wisdom.  These transcripts are "often poorly conserved, unstable, and/or present in few copies" and whether they always have a function is unknown, though Lee suggests that much of this RNA is involved in epigenetic regulation of gene expression. 

lncRNAs were first seen to play a role in genomic imprinting and inactivation of the X-chromosome, with the X-inactive-specific transcript (XIST/Xist) being among the first lncRNAs to be identified in mammals.  Males have 1 X chromosome and females have 2, which means that genes on the X chromosome could be expressed twice as much in females than in males.  This doesn't happen, however, and lncRNA is part of the reason for this.
Nowhere is the abundance of lncRNA more evident than the X-inactivation center (Xic). To balance X-chromosome gene expression between males and females, the Xic on the mammalian X chromosome controls the initiation steps of XCI through a series of RNA-based switches. Today, the Xic serves as a model for understanding epigenetic regulation by lncRNA.
Xist codes for a long piece of RNA that is never translated; the RNA coats the inactive X-chromosome, which results in the silencing of its genes, though it is complicated -- Xist itself is regulated by two other lncRNAs, with downstream effects.  

Lee writes that
"[A]lthough lncRNAs now dominate the Xic, this region was once coding.  Evolution of random XCI 150 million years ago in eutherian mammals coincided with a shift from coding to noncoding space, suggesting that lncRNAs offer distinct advantages over proteins for some forms of epigenetic regulation." 
Why lncRNAs rather than the usual, ubiquitous regulatory elements that turn genes on?  LncRNAs are so large that they seem to address only a unique location in the genome.  Transcription factors, on the other hand, are short and bind with short DNA sequences that often are found in thousands of places in the genome.

Lee presents several classes of lncRNA, those involved in genomic imprinting, which is when only one of the two inherited copies of a gene is expressed; lncRNAs that are involved in non-allelically regulated loci; lncRNAs can activate gene expression as well as repress it; lncRNAs may be found as parts of pseudogenes, from whence they silence or activate the still functional form of the gene.  Lee concludes that much is yet to be discovered about these molecules.  "Indeed, the Wild West is a rich landscape waiting to unfold."

And it is unfolding at a fast rate.  E.g., two papers in the last week's issue of Science document epigenetic involvement in embryonic stem cell pluripotency (here), and epigenetic influences on gene expression as a response to metabolic state (here).  Epigenetics is being over- and too often improperly applied, by people who'd like a simple yet rigorous, scientific explanation for a complex trait, but, like genetics itself, the field is developing to the point where it is possible to begin to sort fact from fiction.

What we don't know
But, just as single genes aren't the explanation for every trait or illness, epigenetics isn't going to be the explanation either.  Naturally enough, we always try to make complete stories from incomplete data -- before we knew about short RNAs or DNA methylation, we thought we understood gene expression.  But, every age has its 'normal science,' as Thomas Kuhn called it in "The Structure of Scientific Revolutions."  It's only when enough challenges arise to that normal science that understanding can broaden and build those challenges into a new and different picture.  The picture may change to encompass new data, but the sense that we actually understand does not; we always think we do.  We never know how much we don't know. 

*Nice introductions to epigenetics:
Neuroscientist Kevin Mitchell nicely sums up the history of epigenetics, and its current trendiness -- and misapplication -- in a two-part blog series starting here.

Here's a quick YouTube discussion.


Hollis said...

What an exciting time! We keep finding more examples of types of information beyond genes, in development and inheritance. You would think that by now everyone would realize that the old dogma is dead. If nothing else, all these “surprising” discoveries should make it clear that we don’t understand how things work, though we’re making progress. But not. Those who argue epigenetics has a major role, e.g. in evolution, are expected to defend it to the last details (not yet available) while old-school geneticists don’t have to defend their model, even though there has never been enough information to support it (unless one looks at pea flowers ... maybe).

Five years ago, I left a population genetics program because of a very basic disagreement with the professor, in a class on genetics of evolution. Small mutations are not the only mechanism for generating variation, there are many more forms of heritable information that can change. I remember well his snide remark re epigenetics -- a very minor role, at most.

Anne Buchanan said...

Ah yes. You'd think we'd all be much more humble about what we don't know! After all, if we think we understand everything, why keep doing science?

Hollis said...

! :-)