Q re: New Yorker Article about epigenomics

Buzz Bloom

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Epigenomics is the study of the effects of chromatin structure on the function of the included genes.
Epigenetics is (a) the study of the processes involved in the genetic development of an organism, especially the activation and deactivation of genes, and (b) the study of heritable changes caused by the activation and deactivation of genes without any change in DNA sequence.
The following link is to an article in the online New Yorker:
Here are some quotes that I think captures much about the core nature of these fields.
“The remarkable thing about workers and gamergates,” Yan told me, “is that they are almost genetically identical.” The gene sequence before and after the transition is the same. Yet, as DNA methyl groups or histone modifications get shifted around those gene sequences, the worker transforms into a gamergate, and virtually everything about the insect’s physiology and behavior changes. “We’re going to solve how the change can have such a dramatic effect on longevity,” Reinberg said. “It’s like one twin that lives three times longer than the other”—all by virtue of a change in epigenetic information.​

The medical impact of epigenetics remains to be established, but its biological influence has been evident for nearly a decade. Diffuse, mysterious observations, inexplicable by classical genetics, have epigenetic explanations at their core. When a female horse and a male donkey mate, they produce a longer-eared, thin-maned mule; a male horse and a female donkey typically generate a smaller, shorter-eared hinny. That a hybrid’s features depend on the precise configuration of male versus female parentage is impossible to explain unless the genes can “remember” whether they came from the mother or the father—a phenomenon called “genomic imprinting.” We now know that epigenetic notations etched in sperm and eggs underlie imprinted genes.​

Perhaps the most startling demonstration of the power of epigenetics to set cellular memory and identity arises from an experiment performed by the Japanese stem-cell biologist Shinya Yamanaka in 2006. Yamanaka was taken by the idea that chemical marks attached to genes in a cell might function as a record of cellular identity. What if he could erase these marks? Would the adult cell revert to an original state and turn into an embryonic cell? He began his experiments with a normal skin cell from an adult mouse. After a decades-long hunt for identity-switching factors, he and his colleagues figured out a way to erase a cell’s memory. The process, they found, involved a cascade of events. Circuits of genes were activated or repressed. The metabolism of the cell was reset. Most important, epigenetic marks were erased and rewritten, resetting the landscape of active and inactive genes. The cell changed shape and size. Its wrinkles unmarked, its stiffening joints made supple, its youth restored, the cell could now become any cell type in the body. Yamanaka had reversed not just cellular memory but the direction of biological time.
A question occurred to me in reading the article.
Is there any evidence to support the idea that the mechanism of chromatin structure effecting the functioning of an organism's DNA was a necessary prerequisite for multi-cellular creatures to evolve?​
Since bacteria and archaea never evolved into multi-cell organisms, do they have any protein wrappers on their DNA that effect their gene expression? Are there any primitive single-cell eukaryotes without such protein wrappers?
 

jim mcnamara

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Answer: yes, prokaryotes do have DNA methylation, and some types of methylation that do not occur in Eukaryotes.
And no, I do not see any support for DNA methylation being a requisite for the evolution of Eukaryotes.

Start here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1594586/

And pointing out an assumption in your question: eukaryotes are somehow special compared to prokaryotes. Eukaryotes in fact are the result of endosymbionts that were originally all free living prokaroytic organisms. Mitochondria have plasmid DNA, ring shapes identical to bacteria.
 

Ygggdrasil

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Is there any evidence to support the idea that the mechanism of chromatin structure effecting the functioning of an organism's DNA was a necessary prerequisite for multi-cellular creatures to evolve?
Chromatin structure is thought to be an important mechanism for allowing cell differentation in order so that one genome can encode many different cell types. While there are some simple multicellular communities of bacteria, they do not show differentiation to the same extent as multicellular eukaryotic cells. However, even though all multicellular life makes use of chromatin, chromatin is probably not a unique solution to the problem of multicellularity. Certainly, some of the basic mechanisms that regulate chromatin differ among different eukaryotes (for example, plants, which evolved multicellularity independently of animals, have many more types of DNA methylation than animals). Evolving a sophisticated mechanism for controling gene expression in a way that can stably pass between cell divisions is definitely a prerequisite for the evolution of multicellularity, however.

Since bacteria and archaea never evolved into multi-cell organisms, do they have any protein wrappers on their DNA that effect their gene expression? Are there any primitive single-cell eukaryotes without such protein wrappers?
There are some histone-like proteins in bacteria that may help coordinate and regulate gene expression (http://science.sciencemag.org/content/333/6048/1445.long), but how they function is still not very clear. All eukaryotes, including simple single-celled eukaryotes like yeast, have the nucleosomes and associated proteins that form chromatin. In yeast, changes to chromatin structure underlie changes in gene expression that occur when yeast transition from one environment to another (and in fact, many chromatin regulatory proteins were disovered by studying these processes in single-celled yeast).

Because chromatin is ubiquitous among all eukaryotes, including the unicellular ones, chromatin is certainly not sufficient for multicellularity nor did it evolve specifically for multicellularity. Chromatin may have initially evolved as a means of defending against retroviruses, transposons, and other "selfish" genetic elements (http://www.sciencedirect.com/science/article/pii/S0092867413012348).
 

Buzz Bloom

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Hi @jim mcnamara and @Ygggdrasil:

I gather from both your posts that you agree that protein wrappers for DNA are found in living cells for all three domains: bacteria, Archaea, and eukaryotes, and that this mechanism for controlling the activity of genes is not sufficient for multi-cellular forms to evolve. I also understand that this mechanism may have evolved independently in all three domains as a defense against viruses, etc.

Jim says
I do not see any support for DNA methylation being a requisite for the evolution of Eukaryotes.
Ygggdrasil says
Chromatin structure is thought to be an important mechanism for allowing cell differentiation
I interpret Ygggdrasil's quote as saying that proteins wrappers are necessary for multi-celled creatures to evolve, since the multiple cells of such an organism must be differentiated in order for the different kinds of tissues needed for such organisms to exist (although the wrappers are not sufficient to make this happen).

I would much appreciate Jim's response regarding this point.

I would also appreciate anyone's suggestions about what additional mechanisms, together with the wrappers, might plausibly be sufficient for multi-celled creatures to evolve. I understand that the eukayotes have the additional benefit of a nucleus and also organelles, but I am not aware of any role of these features as the basis for multi-cell organisms to evolve.

Regards,
Buzz
 

jim mcnamara

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This proposes a single mutation to protein which resulted in multicellularity. IMO, this conclusion is far from a done deal, but does not necessarily involve chromatin.

Evolution of an ancient protein function involved in organized multicellularity in animals.
Abstract

Douglas P Anderson, Dustin S Whitney, Victor Hanson-Smith, Arielle Woznica
William Campodonico-Burnett, Brian F Volkman, Nicole King, Joseph W Thornton
Kenneth E Prehoda

Article DOI: http://dx.doi.org/10.7554/eLife.10147

Abstract DOI: http://dx.doi.org/10.7554/eLife.10147.001

Abstract
To form and maintain organized tissues, multicellular organisms orient their
mitotic spindles relative to neighboring cells. A molecular complex scaffolded
by the GK protein-interaction domain (GKPID) mediates spindle orientation in
diverse animal taxa by linking microtubule motor proteins to a marker protein on
the cell cortex localized by external cues. Here we illuminate how this complex
evolved and commandeered control of spindle orientation from a more ancient
mechanism. The complex was assembled through a series of molecular exploitation
events, one of which – the evolution of GKPID’s capacity to bind the cortical
marker protein – can be recapitulated by reintroducing a single historical
substitution into the reconstructed ancestral GKPID. This change revealed and
repurposed an ancient molecular surface that previously had a radically
different function. We show how the physical simplicity of this binding
interface enabled the evolution of a new protein function now essential to the
biological complexity of many animals.

DOI: http://dx.doi.org/10.7554/eLife.10147.001
 

Ygggdrasil

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This proposes a single mutation to protein which resulted in multicellularity.
I don't think that the article is claiming that that single mutation alone is responsible for multicellularity. The paper describes the evolution of a system required for orienting the mitotic spindle, which is only one of many changes required for multicellularity.

I would also appreciate anyone's suggestions about what additional mechanisms, together with the wrappers, might plausibly be sufficient for multi-celled creatures to evolve. I understand that the eukayotes have the additional benefit of a nucleus and also organelles, but I am not aware of any role of these features as the basis for multi-cell organisms to evolve.
In general, the question of what molecular and genetic changes enable multicellularity is not well understood. Here is one hypothesis regarding some of the changes required:
To solve the mystery of how multicellular life persisted, scientists are suggesting what they call “ratcheting mechanisms.” Ratchets are devices that permit motion in just one direction. By analogy, ratcheting mechanisms are traits that provide benefits in a group context but are detrimental to loners, ultimately preventing a reversion to a single-celled state, said Libby and study co-author William Ratcliff at the Georgia Institute of Technology in Atlanta.

In general, the more a trait makes cells in a group mutually reliant, the more it serves as a ratchet. For instance, groups of cells may divide labor so that some cells grow one vital molecule while other cells grow a different essential compound, so these cells do better together than apart, an idea supported by recent experiments with bacteria.
http://www.astrobio.net/news-exclusive/multicellular-life-evolve/
 

jim mcnamara

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I do not think it is well understood, also, and sometimes articles in places like the New Yorker Magazine, aimed at non-scientists, do not do more than fuzz things up.

My point is a lot like what you're saying - that the chromatin approach or any one single other approach is not necessarily a foregone conclusion.

For me, the real issue is plants. They seem to have evolved multicellular living and cell differentiation independently several different times. It'd be nice if some plant-like beastie would cooperate and do that hat trick again for us in the lab.
 
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I think this discussion illustrates the problem with trying to explain evolution at the level of the gene. Evolution describes a change process that is driven largely by the environment and genetic expression is also a function of the internal environment of the cell and the external environment, there is a lot of work on the effect of certain nutrients and nutrient states and certain inter cellular messengers like pheromones. I wonder if many of the external messages from other organisms in a community become more important over time and replace some of the intracellular processes controlling gene expression. In complex organisms it is the messages from the surrounding cells that allow for cell differentiation and a sort of spacial and functional awareness. The idea of these changes being nutrient dependent and pheromone driven allows for much faster adaptive changes that are not down to chance variations being selected.
I don't know what I think about these ideas myself yet so I'm interested in the various views.
 

Ygggdrasil

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FYI for those who read the New Yorker piece that @Buzz Bloom linked to in the OP, various scientists have been pretty critical of Mukherjee's presentation of the science he discusses:
Everyone I know who has read The Emperor of All Maladies gives it high praise. I wish I could say the same for Mukherjee’s New Yorker piece. When I read it at the behest of the two readers, I found his analysis of gene regulation incomplete and superficial. Although I’m not an expert in that area, I knew that there was a lot of evidence that regulatory proteins called “transcription factors”, and not “epigenetic markers” (see discussion of this term tomorrow) or modified histones—the factors emphasized by Mukherjee—played hugely important roles in gene regulation. The speculations at the end of the piece about “Lamarckian evolution” via environmentally induced epigenetic changes in the genome were also unfounded, for we have no evidence for that kind of adaptive evolution. Mukherjee does, however, mention that lack of evidence, though I wish he’d done so more strongly given that environmental modification of DNA bases is constantly touted as an important and neglected factor in evolution.

Unbeknownst to me, there was a bit of a kerfuffle going on in the community of scientists who study gene regulation, with many of them finding serious mistakes and omissions in Mukherjee’s piece. There appears to have been some back-and-forth emailing among them, and several wrote letters to the New Yorker, urging them to correct the misconceptions, omissions, and scientific errors in “Same but different.” As I understand it, both Mukherjee and the New Yorker simply batted these criticisms away, and, as far as I know, will not publish any corrections.
https://whyevolutionistrue.wordpress.com/2016/05/05/the-new-yorker-screws-up-big-time-with-science-researchers-criticize-the-mukherjee-piece-on-epigenetics/

In a second post, two researchers provide additional criticisms of some of the claims from the New Yorker piece that are relevant to the topics discussed in this thread. For example:
The lambda phage switch mechanism is one well-known example of how regulatory proteins can be used to switch a gene “on”, with the gene then persisting in this ‘on’ state in the absence of the protein/signal that first switched it on. The mechanism is an instantiation of positive feedback (see Introduction). The more detailed explanation is readily apparent, and does not involve extra layers of information. The mechanism has been well-established in many cases in higher organisms as well.
This is once again subscribing to the view that chromatin structure is the primary determinant of cellular and organismal states. If that is the view, then the question must be asked – if you could magically change chromatin structure at specific genomic locations, why would cell physiology alter? If the answer is that “this will allow regulatory proteins to bind at these specific sequences,” then the question becomes why invoke a mysterious mechanism for targeted chromatin structure changes with secondary binding of regulatory proteins, when a primary event of binding of these proteins accomplishes both steps?
https://whyevolutionistrue.wordpress.com/2016/05/06/researchers-criticize-the-mukherjee-piece-on-epigenetics-part-2/

[Edit 5/7: Mukherjee has posted a response to some of the criticisms of his article: http://www.stsiweb.org/an-epigenetics-controversy/]
 
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