The Imprinter of All Maladies

Any sufficiently convoluted explanation for biological phenomena is indistinguishable from epigenetics.

Epigenetics

Use of the word “epigenetics” over time

Epigenetics is everywhere. Nary a day goes by without some news story or press release telling us something it explains.

Why does autism run in families?  Epigenetics.
Why do you have trouble losing weight? Epigenetics.
Why are vaccines dangerous? Epigenetics.
Why is cancer so hard to fight? Epigenetics.
Why a cure for cancer is around the corner? Epigenetics.
Why your parenting choices might affect your great-grandchildren? Epigenetics.

Epigenetics is used as shorthand in the popular press for any of a loosely connected set of phenomenon purported to result in experience being imprinted in DNA and transmitted across time and generations. Its place in our lexicon has grown as biochemical discoveries have given ideas of extra-genetic inheritance an air of molecular plausibility.

Biologists now invoke epigenetics to explain all manner of observations that lie outside their current ken. Epigenetics pops up frequently among non-scientists in all manner of discussions about heredity. And all manner of crackpots slap “epigenetics” on their fringy ideas to give them a veneer of credibility. But epigenetics has achieved buzzword status far faster and to a far larger extent than current science justifies, earning the disdain of scientists (like me) who study how information is encoded, transferred and read out across cellular and organismal generations.

This simmering conflict came to a head last week around an article in The New Yorker, Same but Different” by Siddhartha Mukherjee that juxtaposed a meditation on the differences between his mother and her identical twin with a discussion of the research of Rockefeller University’s David Allis on the biochemistry of DNA and the proteins that encapsulate it in cells, that he and others believe provides a second mechanism for the encoding and transmission of genetic information.

Although Mukherjee hedges throughout his piece, the clear implication of the story is that Allis’s work provides an explanation for differences that arise between genetically identical individuals, and even suggests that they open the door to legitimizing the long-discredited ideas of the 19th century naturalist Jean-Baptiste Lamarck who thought that organisms could pass beneficial traits acquired during their lifetimes on to their offspring.

The piece earned a sharp rebuke from many scientists, most notably Mark Ptashne who has long led the anti-epigenetics camp, and John Greally, who published a lengthy take-down of Mukherjee’s piece on the blog of evolutionary biologist Jerry Coyne.

The dispute centers on the process of gene regulation, wherein the levels of specific sets of genes are tuned to confer distinct properties on different sets of cells and tissues during development, and in response to internal and external stimuli. Gene regulation is central to the encoding of organismal form and function in DNA, as it allows different cells and even different individuals of a species to have identical DNA and yet manifest different phenotypes.

Ptashne has studied the molecular basis for gene regulation for fifty years. His and Greally’s critique of Mukherjee, or really Allis, is rather technical, and one could quibble about some of the specifics. But his main points are simple and difficult to refute:

  • There is essentially no evidence to support the idea that chemical modification of DNA and/or its accompanying proteins is used to encode and transmit information over long periods of time.
  • Rather than representing a separate system for storing and conveying information, a wide range of experiments suggests that the primary role of the biochemistry in question is to execute gene expression programs encoded in DNA and read out by a diverse set of proteins known as transcription factors that bind to specific sequences in DNA and regulate the expression of nearby genes.

In one way this debate is incredibly important because it is ultimately about getting the science right. Mukherjee’s piece contained several inaccurate statements and, by focusing on one aspect of Allis’s work, gave an woefully incomplete picture of our current understanding of gene regulation.

Any system for conveying information about the genome – which is what Mukherjee is writing about – has to have some way to achieve genomic specificity so that the expression of genes can be tuned up or down in a non-random manner. Transcription factors, which bind on to specific DNA sequences, provide a link between the specific sequence of DNA and the cellular machines responsible for turning information in DNA into proteins and other biomolecules. Small RNAs, which can bind to complementary sequences in DNA, also have this capacity.

But there is scant evidence for sequence specificity in the activities of the proteins that modify DNA and the nucleosomes around which it is wrapped. Rather they get their specificity from transcription factors and small RNAs. That doesn’t render this biochemistry unimportant – the broad conservation of proteins involved in modifying histones shows they play important roles – but ascribing regulatory primacy to DNA methylation and histone modifications is not consistent with our current understanding of gene regulation.

Something is, however, getting lost in this back-and-forth , as one might come away with the impression that this is disagreement about whether cells and organisms can transmit information in a manner above and beyond DNA sequence. And this is unfortunate, because there really is no question about this. Ptashne and Allis/Mukherjee are arguing about the molecular details of how it happens and about how important different phenomena are.

Various forms of non-Mendelian information transfer are well established. The most important of which happens in every animal generation, as eggs contain not only DNA from the mother, but also a wide range of proteins, RNAs and small molecules that drive the earliest stages of embryonic development. The particular cocktail left by the mother can have profound effects on the new organism – so called “maternal effects”. These effects can be the result of both the mothers genotype, the environment in which she lives, and, in various ways, her experiences during her life. (Such phenomena are not limited to multicellular critters – single-celled organisms distribute many molecules asymmetrically when they divide, conferring different phenotypes to their different genetically identical offspring).

Many maternal effects have been studied in great detail, and in most cases the transmission of state involves the transmission of different concentrations and activities of proteins (including transcription factors) and RNAs. That is the transmitted DNA is identical, but the state of the machinery that reads out the DNA is different, resulting in different outcomes.

However there are some good examples in which modifications to DNA play an important role in the transmission of information across generations – most notably with “imprinting”, in which an organism preferentially utilizes the copy of a gene it got from one of its parents independent to the exclusion of the other in a way that appears to be independent of the sequence of the gene. Imprinting, which is a relatively rare, but sometimes important, phenomenon appears to arise from parent-specific methylation of DNA.

Could the histone modifications that Allis studies and Mukherjee focuses on also carry information across cell divisions and generations? Sure. Our understanding of gene regulation is still fairly primitive, and there is plenty of room for the discovery of important inheritance mechanisms involving histone modification. We have to keep an open mind. But the point the critics of Mukherjee are really making is that given what is known today about mechanisms of gene regulation, it is bizarre bordering on irresponsible to focus on a mechanism of inheritance that only might be real.

And Mukherjee is far from the only one to have fallen into this trap. Which brings me to what I think is the most interesting question here: why does this particular type of epigenetic inheritance involving an obscure biochemical process have such strong appeal? I think there are several things going on.

First, the idea of a “histone code” that supersedes the information in DNA exists (at least for now) in a kind of limbo: enough biochemical specificity to give it credibility and a ubiquity that makes is seem important, but sufficient mystery about what it actually is and how it might work that people can imbue it with whatever properties they want. And scientists and non-scientists alike have leapt into this molecular biological sweet spot, using this manifestation of the idea of epigenetics as a generic explanation for things they can’t understand, a reason to hope that things they want to be true might really be, and as a difficult to refute, almost quasi-religious, argument for the plausibility of almost any idea linked to heredity.

But there is also something more specifically appealing about this particular idea. I think it stems from the fact that epigenetics in general, and the idea of a “histone code” in particular, provide a strong counterforce to the rampant genetic determinism that has dominated the genomic age. People don’t like to think that everything about the way they are and will be is determined by their DNA, and the idea that there is some magic wrapper around DNA that can be shaped by experience to override what is written in the primary code is quite alluring.

Of course DNA is not destiny, and we don’t need to evoke etchings on DNA to get out of it. But I have a feeling it will take more than a few arch retorts from transcription factor extremists to erase epigenetics from the zeitgeist.

This entry was posted in epigenetics, gene regulation, My lab, science. Bookmark the permalink. Both comments and trackbacks are currently closed.

26 Comments

  1. Chad
    Posted May 10, 2016 at 2:35 pm | Permalink

    I know the focus of Mukherjee’s article and the criticism was humans and animals…but there is hard evidence of DNA methylation transmitting heritable changes in plants. The extent of it or its long-term stability beyond 7-8 generations is unknown, but the evidence is clearly there.

    • Michael
      Posted May 11, 2016 at 10:01 am | Permalink

      Bingo!

      • michael
        Posted May 11, 2016 at 11:08 am | Permalink

        and this, its probably tRNA frags doing the dirty hereditary work:

        ↵ Sharma, (2016) Biogenesis and function of tRNA fragments during sperm maturation and fertilization in mammals. Science 351, 391–396
        ↵ Chen, Q., Yan, M., Cao, Z., Li, X., Zhang, Y., Shi, J., Feng, G. H., Peng, H., Zhang, X., Zhang, Y., Qian, J., Duan, E., Zhai, Q., Zhou, Q. (2016) Sperm tsRNAs contribute to intergenerational inheritance of an acquired metabolic disorder. Science 351, 397–400

  2. Posted May 10, 2016 at 3:31 pm | Permalink

    The whole spat seems overblown to me. Yes, epigenetics is a buzzword, which is why I generally avoid it. But the reality is that histone and DNA modifications do influence transcription of specific genes! There are countless examples of this occurring within a single organism (heritability is another question).

    It seems like the primary objection boils down to the fact that the histone and DNA modifications are just one link in the causal chain between environment and phenotype. They get their DNA sequence specificity from proteins like transcription factors, which are ultimately more important/informative. But that doesn’t mean histone and DNA modifications aren’t involved in regulating gene expression– of course they are. And because of that, they are probably part of the mechanism by which identical twins end up different. I haven’t seen that fact clearly acknowledged by Mukherjee’s critics.

    Regarding the question of why people are so hooked on the concept of epigenetics, I think your second theory is right. Genetics seems so fatalistic to people, so they love the idea that the DNA code can effectively be modified. I do think that if people really understood how gene regulation works, particularly the fact that transcription factors are often highly responsive to signals that reflect environment, it would take a lot of the shine out of the concept of epigenetics.

    • Mark Ptashne
      Posted May 11, 2016 at 12:24 pm | Permalink

      Sorry I don’t follow this. What do you mean by “of course they are”? Some 100 proteins are required to transcribe a gene – sometimes acetylaters, whatever their real substrates. How does that show that they are involved in “regulation”?

      • Posted May 13, 2016 at 4:01 pm | Permalink

        I don’t see the relevance of the fact that 100 proteins are required to transcribe a gene. The question is, does acetylation/methylation of histones/DNA play a causal role in determining the rate of gene transcription? Genetics isn’t my primary area of expertise so I don’t claim any special knowledge in this area, but it certainly is commonly accepted in my field (neurobiology) that histone acetylation influences transcription rates. Is that incorrect? If so, many researchers have got it wrong.
        http://www.nature.com/nsmb/journal/v20/n3/abs/nsmb.2470.html

        • Keith A. Maggert
          Posted May 15, 2016 at 6:20 am | Permalink

          Histone modifications are part of the process of regulating transcription, but do not control it. This may appear to be a thinly-sliced distinction, but it is not.

          Bear with an analogy:
          the pressure of a foot on the brake pedal affects the speed of a car, but it’s the driver’s control of the foot that is really “in charge.” You can certainly cut brake-lines and the car goes faster, so superficially, the foot appears to control car speed. But the question we’re all after is “how is car speed controlled?” And the answer is “the driver.” In this case, of course, the foot is acetylation, the head is the transcription factor.

          It’s a general confusion of these two points that has brought us to our current confusion. The *problem* is that, as you point out, many think that acetylation or methylation *can* be the ultimate master: regulatory and self-perpetuating. The former (regulatory) is bogged down by semantics (again the foot is, in a way, regulating, but is that what we’re really trying to understand or talk about..?), but the evidence that histone modifications are self-perpetuating (though mitosis) is so-close-to-zero that it’s zero.

          • Posted May 15, 2016 at 11:30 am | Permalink

            Thanks Keith. This is consistent with what I’ve been taught, as a genetics non-expert with some genetics knowledge. What I’m understanding is that these modifications are a link in the causal chain leading to gene regulation, but they aren’t themselves regulating in the strict sense of the term. They’re essentially an effector mechanism for regulation.

  3. Posted May 10, 2016 at 4:14 pm | Permalink

    Very nice post; thank you. I don’t think any of us has questioned the importance of phenomena like imprinting, but the important thing to remember is that the imprinting itself is coded in the DNA rather than simply being induced by the environment without any genetic basis. It’s the completely nongenetic type of imprinting that’s touted by those who are saying that epigenetics overturns modern evolutionary theory.

  4. Ian Quigley
    Posted May 10, 2016 at 4:25 pm | Permalink

    It also seems possible that most people’s major experience with the transmission of multigenerational information – culture – is something both acquired after birth through experience and passed on down the line, and this familiarity may be a reason why Lamarckianism persists so strongly.

    As for the rest of it, TFs all the way! They buy the booze and turn on the music, whereas active histone mods only make the party look more attractive by helping it hit a critical mass.

  5. Spiny Norman
    Posted May 10, 2016 at 5:28 pm | Permalink

    I found this passage in Mukherjee’s article to be extremely funny: ” For a scientist who has won virtually all of science’s most important prizes except the Nobel (and that has been predicted for years), Allis is ruthlessly self-effacing—the kind of person who offers to leave his name on a chit at the faculty lunchroom because he has forgotten his wallet in the office.”

    The only interaction I’ve ever had with David Allis is reading letters of recommendation that he’s written for various of his trainees. I do not think it betrays any special confidence to say that these letters are remarkable for their adherence to the inverted pyramid style of exposition.

    They typically open with nearly a page of — there’s really no other word for it — lavish self-praise of David Allis and his own contributions to science. Only then do these letters really mention the trainee’s qualifications or accomplishments. Even when Allis seems to really like his trainees, the overriding impression the reader is left with, is that Allis really thinks Allis is very important.

    Even from some of the most notorious egos in molecular biology, I’ve never seen the likes of a David Allis letter of recommendation.

  6. Keith A. Maggert
    Posted May 10, 2016 at 5:37 pm | Permalink

    This may seem ruthlessly self-aggrandizing, but a student and I wrote a short essay on the uses and misuses of “epigenetic,” and some of the problems that arise because of it. If you’re interested, it was published in Genetics last year:
    http://www.genetics.org/content/199/4/887.long

    • Vijay
      Posted May 10, 2016 at 10:06 pm | Permalink

      Thanks Keith, This will be very useful for students to use and critique. Best

  7. Posted May 10, 2016 at 5:38 pm | Permalink

    http://www.homolog.us/blogs/blog/2016/05/06/epigenetics-debacle-do-you-feel-sad-for-sid-mukherjee/

    We have been writing for a long time hyping ‘epigenetics’ by NHGRI-funded big projects, not backed by any evidence. If I remember correctly, Hobart, Davidson and Ptashne wrote a strong letter to stop the ‘epigenome’ project, which was promptly regarded.

    “People don’t like to think that everything about the way they are and will be is determined by their DNA, and the idea that there is some magic wrapper around DNA that can be shaped by experience to override what is written in the primary code is quite alluring.”

    By ‘people’, do you mean scientists? Scientists do have additional responsibilities, when it comes to speculating to public.

    http://www.lhup.edu/~DSIMANEK/cargocul.htm

  8. Flemming Rasmussen
    Posted May 10, 2016 at 5:45 pm | Permalink

    MB – quite enjoyed this blog and find the ‘maternal influence’ paragraph a practical start to the gene regulation discussion. When we expand that narrative to include surrogate mother and adoption influences, the ‘molecular details of how it happens’ phrase you employ brings needed context.
    Somewhere immediately upstream from the ‘different concentrations and activities of proteins (including transcription factors) and RNAs’ you highlight must be a “headwater” of sort linked to our unique “Elementome” (at one level a defined mix/ratio/quantity of our Periodic Table of elements make-up). It is the departure from this point where a seemingly subtle exchange of the terms ‘unique’ and ‘inherent’ is perhaps one of the science narrative’s bigger downfalls; our individual ‘uniqueness’ we know is nonetheless quite plastic! It is from this point of view that I can appreciate the genomic specificity where you assert that the ‘expression of genes can be tuned up or down in a non-random’ manner can be visualized/qualified, and if correct, can also be quantified

  9. Tomas Ekstrom
    Posted May 10, 2016 at 10:02 pm | Permalink

    Interesting discussion. Please read the theory (also with experimental evidence) by Feinberg and Irizarry on the evolutionary relationship between genetics, epigenetic variation and adaptation. A nice way to understand how environment influences phenotypes through the genetically encoded epigenetic dynamics.
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2868296/

  10. Posted May 11, 2016 at 12:55 pm | Permalink

    Perhaps of relevance:

    Alexander Vinogradov (2005) Trends in Genetics 21:633–639

  11. Donald Forsdyke
    Posted May 11, 2016 at 3:06 pm | Permalink

    The Google Books Ngram Viewer lists the emergence of “epigenetics” as in the figure above. However, we might note for 1861:

    Epigenetic: 0.0000001159

    Epigenetics: 0.000000000

    Epigenesis: 0.0000018312

  12. handjive
    Posted May 12, 2016 at 1:35 am | Permalink

    The essay makes has many good points, but it may be way off regarding the future place of epigenetics in the zeitgeist. I expect the strong allure of the idea is so seductive that even a million fine geneticists at a million fine conferences would never purge it from the popular memeosphere.

  13. Frank Griffin
    Posted May 12, 2016 at 1:30 pm | Permalink

    What a fantastic discussion. Not being a geneticist, chemist, or biologist, I cannot attempt to argue the merits or lack of merit of explanations for genetic modification or inheritance. What I can observe, however is the transmission of learned behavior in animals (specifically dogs) across generations. Somehow this trained behavior was passed genetically across generations (“pointing” is a good example). “A cat acts like a cat even if it has never seen another cat”. Some mechanism is in fact carrying these behavioral lessons across generations. My Dalmatian still pointed whenever it smelled a bird and it had never been taught that behavior. It was “genetically” handed down from a prior generation who had been taught that behavior.

  14. julie gay
    Posted May 12, 2016 at 5:18 pm | Permalink

    Couldn’t that behavior have been observed and preserved by breeding. Could the distant cousin of your dog been born to freeze at the sight of possible f
    ood and someone manipulated this natural behavioral quirk to their benefit?

  15. Utpal Davé
    Posted May 13, 2016 at 6:53 am | Permalink

    Thanks for your post. The language within this field has been imprecise. So, it was not surprising that the Mukhergee article had some overstatements.

    one can find the following overstatements in the scientific literature:
    epigenetic = histone modification
    epigenetic = gene expression
    histone modification = gene expression

    Now, within cancer biology the term epigenetic therapy is commonly used since some small molecules that can inhibit the enzymatic functions of histone modifying enzymes cause tumor regression. It is not clear what the substrates are for such enzymes, histones or other proteins. Thus, not clear whether the drugs are perturbing a DNA modification. But, now the following:
    epigenetic therapy = gene expression therapy

  16. Posted May 16, 2016 at 1:34 am | Permalink

    Excerpt: Could the histone modifications that Allis studies and Mukherjee focuses on also carry information across cell divisions and generations?

    My comment: Allis is co-author of “Every amino acid matters: essential contributions of histone variants to mammalian development and disease” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082118/

    All serious scientist know that energy-dependent RNA-mediated amino acid substitutions differentiate all cell types in all living genera. Some of them know that virus-driven energy theft is the source of all pathology. But, if someone like Allis admitted that he knows that, the damage done to the evolution industry could not be repaired. Thus, everyone must keep pathology for the neo-Darwinists to keep their theories.

    Do we have a deal, or not?

  17. Posted May 19, 2016 at 9:11 am | Permalink

    A nice post — with one of the best titles imaginable. Well done.

  18. Brittany
    Posted May 19, 2016 at 4:24 pm | Permalink

    Well written and a very dogged attempt at downplaying the multiple fields and vast advances that have been made in epigenetic.

    While I would love to spend my evening picking these things apart, I have no patients to reread any of it.

    So I will focus on the bullet points. #1

    “There is essentially no evidence to support the idea that chemical modification of DNA and/or its accompanying proteins is used to encode and transmit information over long periods of time.”

    1. What is a “long periods of time?” The lifetime of individual, perhaps? Tell me how certain populations of neurons in your brain exist throughout your lifetime, if there are no chemical modification of DNA involved? What continues to repress liver genes from being expressed? What maintains the transcriptional profile? And what directs the continuous expression of the relevant genes? The biochemistry involved in actually capturing the ‘snapshot’ of the transcription factor/ DNA binding events should give us a hint. Its hard work to capture these events–temporally. To me this would suggest they can’t really be responsible for a vast majority of such ongoing processes. Besides imagine the metabolic demands, for a cell that lives 50-100 years?

    2. Why do we even distinguish levels of pluripotency if all that bloody matters is transcription factors?

    3. Furthermore, tell me about the complications of iPSC technology? If there is no form of ‘cellular memory’ or what you very inappropriately call ‘experience being imprinted on the DNA’ in an early paragraph, then why is it so difficult to reprogram cells? Why does the ‘history’ of the previous lineage consistently cause complications in reprogramming? And why are some cell types easier to reprogram?

    And your #2
    “Rather than representing a separate system for storing and conveying information, a wide range of experiments suggests that the primary role of the biochemistry in question is to execute gene expression programs encoded in DNA and read out by a diverse set of proteins known as transcription factors that bind to specific sequences in DNA and regulate the expression of nearby genes.”

    1. It is a very quaint idea you seem to have. That it simple comes down to on and off switches, or the “biochemistry involved is primarily to execute gene expression programs.”
    But if there really is no further hierarchal structure, then explain to me just how we are supposed to believe transcription factors serendipitously find their ~10 bp targets in a human nucleus- with a diameter of 6um and 2 meters of DNA–or what is equivalent to 25 miles of thin thread packed tightly into a tennis ball. What organises the DNA into domains that allows efficient patterns of expression? What drives TF targeting?

    2. Somewhere, someone wrote, ‘its not surprising we get cancer, its surprising how rarely we get cancer’. Well the surprise is the vast network of epigenetic regulators that maintain the transcriptional profile. The surprise is that its not simply an ‘on/off’ switch system.

    3. Consider drug addiction. You find the same ‘epigenetic’ pathways important for establishing cell fate and maintaining cell identity being high jacked/up-regulated in the instance of drug addiction. To me, this is a very clever system of cellular memory, which is otherwise inexplicable.

    I could really go on. But alas its bedtime.

    • Torbjörn Larsson
      Posted May 22, 2016 at 9:48 am | Permalink

      Brittany,

      I am not a biologist, but it seems to me your #1 & #2 Qs all have As in Greally’s “take down” @ Coyne’s blog linked to in Eisen’s article. Enjoy!

7 Trackbacks