Why I’m a Dinosaur

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There has been much discussion, here and elsewhere, on ‘epigenetics’, broadly understood as the control of gene expression. People who cling to ‘classical’ models are portrayed, by revolutionaries and their cheerleaders, as dinosaurs standing in the way of progress.

I could perhaps explain, to any interested bystander, my own rationale for my position, since I’ve requested that of others.

Those of us taught molecular biology between the 1960’s and the noughties assimilated a model of gene regulation that started with the classic work of Jacob and Monod on the lac operon.

The structural genes – the parts coding for actual protein, by transcription into mRNA and translation – are flanked by regions to which transcription factors bind. Transcription proceeds in one direction only (a DNA strand has 2 directions due to the asymmetry of the ribose links). ‘Upstream’ of the protein regions, factors (proteins or RNAs) bind and block or promote the activity of transcription enzymes. In the case of lac, binding represses. So if there is no lactose, the enzymes are not produced. Lactose causes the disassociation of the repressor and the enzymes for its metabolism are produced. Neat, huh?

Now, the classical operon is a prokaryotic feature. Prokaryotes have no histones, and they appear to lack DNA methylation mechanisms, so there can be no involvement of these extra layers. Analogies to ‘memory’ are rather strained. The bound lac repressor is a ‘memory’ the way someone hanging on to one’s ankles is a memory of that person!

Modern eukaryotes spool their genomes on histones. This causes an extra problem/opportunity, beyond basic DNA management, in getting transcription turned on or off. If there is no transcription to do, the DNA is tightly wound on the spools, which involves their methylation (methyl groups are hydrophobic, so cause tightening in the presence of water). If transcription is required, conversely, the methyl groups need removing, and further relaxation can be provided by acetylation. And what causes these changes? Ultimately, it’s those transcription factors. Extra elements are introduced into the cascade, but basically the same kind of promoter/repressor system as in prokaryotes initiates the extra work that needs to be done to expose the reading frame to transcription.

DNA methylation again causes the helix to tighten. One sees something very similar in the thymine-uridine distinction between DNA and RNA. Thymine has exactly the same molecular relation to uridine as methylcytosine has to cytosine, the difference being that thymine’s methyl group is permanent and not neighbour-dependent. A-T base pairs in double-stranded DNA cause the helix to be more tightly wound than dsRNA; methylated cytosines means that C-G pairs reinforce this effect, but reversibly.

These mechanisms provide an additional means of control compared to prokarotes – but the much stronger claim is that they are a separate means of control – that control is by such modification instead of transcription factor binding.

Now if, parallel to all this, one buys the notion that evolution happens, and that eukaryotes derive from prokaryotes, then clearly the basic system would be expected to be one of promoter/repressor binding, subsequently amended to extend to histone modifications and the additional, novel (and by no means universal) mechanism of DNA methylation. It seems unlikely that a completely separate system of regulation would arise driven by histone changes, when histone changes must occur anyway.

If, conversely, one thinks evolution does not happen, and one is further seduced by superficial resemblance and analogy, the idea that the histone and DNA changes constitute a separate level of control seems to hold considerable appeal. There’s no problem with a Designer choosing one mechanism in prokaryotes and another in euks. But the inconvenient fact is that the cascade, as far as has been elucidated, starts with TFs. So had Mukherjee given more (and appropriate) weight to transcription factors, he would pretty much have been writing an article on 60 year old molecular biology. Instead, he’s describing a revolution that hasn’t happened yet.

Histone/DNA methylation codes are not impossible, they just seem very unlikely to people with a particular background. One can invoke old saws about Kuhn, and revolutions proceeding death by death, but one also needs hard data.

196 thoughts on “Why I’m a Dinosaur”

  1. stcordova,

    […] like maybe because I got my description from mainstream literature rather than naysayers at TSZ.

    So how long has the histone code been mainstream?

    And worse, the description agrees with the themes in that hated New Yorker article.

    Only if you are (for some odd reason) determined for that side to ‘win’ the issue. You might answer my earlier question about control of the cascade. Deacetylation does not happen by accident. So what (if not the TF) opens the door so that the TF can bind?

  2. Sal’s apparent reason for preference of a given paradigm is that it is (in some way) opposed by the likes of Moran, Graur, Coyne and us nonentities at TSZ.

    This is an example of a much more general phenomenon of contrarianism where epigenetics is concerned.

  3. The chances of Sal being right against Coyne, Moran and Graur would make a good working definition of zero.

  5. Allan,

    might answer my earlier question about control of the cascade.

    No one knows what is central and whether there is any central issue in gene regulation. It’s premature. I provide one example where the cascade is triggered proximally by the RNA-induced silencing complex (See below).

    I said histone states can block (as in prevent transcription factors from binding). Do you agree or disagree with that statement. Do you agree of disagree with the diagram I just posted from Nature Reviews.

    I hardly think what I provided is fringe, but rather mainstream. I’m astonished at the flak I’m getting for saying what I said:

    Transcription factors can be BLOCKED by histones

    I supported my point from mainstream literature above.

    I also said:

    Secondly, transcription factors can be blocked if the chromatin is inaccessible, and chromatin inaccessibility or accessibility is often dictated by the histone states

    NOTE: I didn’t say always, I said “often”. Which implies I never said it was impossible for transcription factors to bind if chromatin is in the condensed or some other state. Despite the fact I used the word “often” a straw man argument was put forward that I suggested “always” and hence this strawman was put forward:

    DNA_Jock:

    According to Sal’s naive view, this chromatin is inaccessible and its transcriptional activation is impossible. The data say otherwise.

    Strawman misrepresentation, as demonstrated by what I actually said vs. DNA_jock’s false characterization of what I said.

    Now back to what I actually said:

    Secondly, transcription factors can be blocked if the chromatin is inaccessible, and chromatin inaccessibility or accessibility is often dictated by the histone states

    this compares well to the Nature Review in molecular biology

    histone tail acetylation results in chromatin decondensation, thereby allowing access to transcription factors and other transcription co-activators.

    There are other forms of chromatin remodeling where the remodeling is initiated by siRNA/miRNA protein complexes like RITS: RNA Induced Silencing Complex), not by transcription factors (that appear subordinate to RITS):

    Figure 3: Model for the chromatin remodeling by siRNA/miRNA. siRNA in association with the RNA-induced transcriptional silencing complex can alter the rate of chromosomal transcription in a number of ways. It can directly bind nascent mRNA being transcribed from centromeric heterochromatin preventing its translation. The Ago 1/2 protein of the RITS complex can recruit transcription factors and chromatin-remodeling complexes like SWI/SNF that in turn cause assembly of histone modifying enzymes (viz., HATs, HDACs, etc.). The RITS complex can also recruit methylating enzymes that can either directly methylate CpG regions of centromeric DNA or H3K9 regions on histones associated with the chromosome.

    http://www.hindawi.com/journals/lrt/2012/984754/fig3/

  7. stcordova: Allan’s view is a dinosaur view, and dinosaurs by the way, went extinct.

    Did they, now? Are you prepared to defend that notion? (I’m talking about actual dinosaurs here, not Allan.)

  8. James Chapman,

    Compared to the non-vertebrates, differences between types of vertebrates are minor.

    Exactly. Its all relative. In the end, carbon, hydrogen, phosphorus, oxygen, nitrogen and sulfur unites us all. The irony is at the cell level a prokaryotic cell and a eukaryotic cell are much different then a bird cell and a fish cell.

  9. Allan:

    Sal’s apparent reason for preference of a given paradigm is that it is (in some way) opposed by the likes of Moran, Graur, Coyne and us nonentities at TSZ.

    This is an example of a much more general phenomenon of contrarianism where epigenetics is concerned.

    Graur is the contrarian even by his own admission. In the case of epigenetics and ENCODE, the creationists are with the mainstream and evolutionary biologists like Graur are fringe.

    His rhetoric sounds like a conspiracy theorist rather than a scientist who actually has experiments and lab data to prove his point. I see mostly rhetoric from him, not actual experiments and lab results.

    The NIH ENCODE and RoadmapEpigenomics projects have over half a billion in laboratory research from prestigious institutions around the world and 442 to notch researchers like Ewan Birney (whom Graur calls “the scientific equivalent of Saddam Hussein”).

    I’m fringe on a lot of topics, but not epigenetics. Graur is fringe bordering on conspiracy theorist.

  10. John Harshman: Did they, now? Are you prepared to defend that notion? (I’m talking about actual dinosaurs here, not Allan.)

    Considering Sal’s willingness to take this up with his teachers, I’d say the feathered kind are still alive and clucking.

  11. colewd,

    The irony is at the cell level a prokaryotic cell and a eukaryotic cell are much different then a bird cell and a fish cell.

    They have been separated for much longer since common ancestors, so they should be (though it also depends where you look – mitochondria for example).

  12. petrushka: Considering Sal’s willingness to take this up with his teachers, I’d say the feathered kind are still alive and clucking.

    You, sir, win the internet.

  13. stcordova: The bus can’t go anywhere if the road is blocked by histones.

    Still wrong.
    you really aren’t paying attention, are you? As I said,

    Well, sometimes yes, and (pay attention here) sometimes no. The problem in complex systems is distinguishing cause and effect. When scientists manipulate systems where we can distinguish cause and effect, the evidence to date is on the dinosaur’s side.
    But you seem curiously unwilling to discuss the evidence, or Ptashne & Greally’s cogent argument.
    argumentandum ad incantatem, indeed.
    [Emphasis in original]

    The bus can drive straight through the histone road block, given the right TFs. Hence, the TFs are driving the bus. Your argumentandum ad incantatem, quoting wikipedia or review articles, leaves me singularly unimpressed.
    Unsurprised, too.

  14. stcordova,

    Graur is the contrarian even by his own admission. In the case of epigenetics and ENCODE, the creationists are with the mainstream and evolutionary biologists like Graur are fringe.

    His rhetoric sounds like a conspiracy theorist rather than a scientist who actually has experiments and lab data to prove his point. I see mostly rhetoric from him, not actual experiments and lab results.

    You are kind of confirming my suspicions. It’s not about science, it’s about personality. Or in the case of disputes here, about affiliation. You don’t believe a damn thing I say, simply because I’m here. As I’ve mentioned before, I suspect if one of your esteemed profs socked up and tried to correct some of your misunderstandings here, you’d be the same with them as you are with Jock, Rumraket and I. I would, equally, be very interested what they thought of the views herein expressed by all of us, including you.

    The NIH ENCODE and RoadmapEpigenomics projects have over half a billion in laboratory research from prestigious institutions around the world and 442 to notch researchers like Ewan Birney (whom Graur calls “the scientific equivalent of Saddam Hussein”).

    Yes, we’ve been through this. Lots of money and lots of people, can’t all be wrong yadda yadda. No-one is saying they are wrong about everything. Nobody is saying that genetic regulation does not happen, never involves histones, or that it does not involve widespread interaction. Your approach could use some shading. It is not all black and white.

  15. Allan Miller,

    Sal’s apparent reason for preference of a given paradigm is that it is (in some way) opposed by the likes of Moran, Graur, Coyne and us nonentities at TSZ.

    Are these fellow dinosaurs? 🙂

  16. stcordova,

    Me: might answer my earlier question about control of the cascade.

    Sal: No one knows what is central and whether there is any central issue in gene regulation.

    Not relevant. I already said it is not about centrality but about the causal chain. And people certainly know what lies upstream of TF binding – TFs’ effects on chromatin remodelling. So your Nature quote only supports the New Yorker article if you pretend that you don’t know about the effect of TFs on chromatin.

  17. Allis’s hypothesis is that chromatin remodelling lies at the start of the cascade. This is not a mainstream view.

  18. My question remains: if you wanted to modify a phenotype and wanted the modification to be heritable, what would you modify?

  19. or Ptashne & Greally’s cogent argument

    Ptachne isn’t in the gold standard Epigenetics textbook by Allis.

    I provided a diagram from Nature Reviews proving my assertions that histones can block transcription factors.

    I said:

    histones can block transcription factors.

    Agree or disagree. Notice I didn’t say will, yet you pretend as if I said “WILL rather than CAN.

    Well, sometimes yes, and (pay attention here) sometimes no. The problem in complex systems is distinguishing cause and effect. When scientists manipulate systems where we can distinguish cause and effect, the evidence to date is on the dinosaur’s side.

    Queen bees “phenotype” initiated in part by a substance that is not a transcription factor (namely 10HDA) in the Royal jelly. I pointed to microRNAs to which TFs are subordinate in inducing artificial pluripotency, and microRNAs are not transcription factors. I pointed to the RITS (RNA Induced Transcriptin Silencing) complex which is not a transcription factor, etc. etc. and you Ignore ignore ignore.

    The problem with causal chain arguments in things so complex as life is that it leads to chicken and egg paradoxes. It’s a mostly meaningless argument at some point. One could just as well argue messenger RNAs are primary since without them we die. Oh, dear one could say the same of proteins or ribosomes or whatever, and in the case of chickens we can even argue over the primacy of egg shells to protect the chicken embryo. 🙄

    Trying to define epigenetics around transcription factors is straining meaningless arguments. The Epigenetics textbook goes along the lines that were described in The New Yorker — histones, nucleosomes, DNA methylation. The ENCODE and ROADMAPEpigenomics projects focus on epigenetics in the same way.

    If you want to look at biology exclusively through the lens of transcription factors, that’s up to you, but don’t pretend it is universal nor even mainstream.

    the evidence to date is on the dinosaur’s side.

    Are you and Allan tacitly admitting the dinosaur side is not the perspective in favor?

  20. stcordova,

    If you want to look at biology exclusively through the lens of transcription factors, that’s up to you, but don’t pretend it is universal nor even mainstream.

    Good grief, Sal, I’m not sure you even read what’s said to you, other than to react to the odd trigger phrase. No one has made this claim.

  21. Allan Miller:

    As I’ve mentioned before, I suspect if one of your esteemed profs socked up and tried to correct some of your misunderstandings here, you’d be the same with them as you are with Jock, Rumraket and I.

    The usual condescending litany of “Sal doesn’t understand.”

    Feldensfeld, student of double Nobel Lareate Pauling, was mentioned in a somewhat derogatory fashion at Coyne’s blog. He wrote the chapter for my class reading. Why on Earth would you think they would agree with your side given your side said unflattering things of him?

    Well in any case here is a chapter from the class reading materials that are part of Allis’ textbook on epigenetics. Felsenfeld wrote the first chapter which is available freely online.

    See for yourself if Felsenfeld agrees with you.

    Ptachne’s is listed not in way that at all promotes his viewpoint for Eukaryotic multicellular creatures.

    http://cshperspectives.cshlp.org/content/6/1/a018200.full

    The only paragraph on transcription factors:

    It has been proposed that the definition of an epigenetic mechanism should include, in addition to the property of being maintained through cell division, a requirement for an initial signal, such as expression of a transcription factor, that is not needed once the new state is established (Berger et al. 2009). Behavior of this kind has been described for the glucocorticoid response element in which transient binding of glucocorticoid receptor (GR) to some sites leads to nucleosome remodeling that makes it possible for a modified estrogen receptor molecule to bind after the GR has departed (Voss et al. 2011). It should be kept in mind that most eukaryotic transcription factors do not have long residence times at their binding sites, but turn over rapidly. Certain kinds of chromatin modifications could, in principle, provide a mechanism to integrate signals from multiple transcription factors (Struhl 1999).

    The only paragraph on Ptachne

    Actual examples of such systems were found somewhat later in the lac operon of Escherichia coli (Novick and Weiner 1957), and in the lambda phage switch between lysogenic and lytic states (Ptashne 1992). Functionally equivalent models could be envisioned in eukaryotes: The kinds of self-stabilizing inhibitory and stimulatory mechanisms observed in lambda phage are in fact seen in greatly more complex form in higher organisms. In the sea urchin embryo, for example, development proceeds through the establishment and progression of a series of self-stabilizing regulatory networks. However, it is important to recognize an essential difference between the prokaryotic and eukaryotic systems

    Exactly the criticism I leveled against Henikoff who dismissed histones roles in eukaryotic epigenetics because prokaryotes don’t have them.

    In contrast, Fesenfeld said:

    The ultimate connection to detailed mechanisms began with the critical demonstration by Allis and coworkers (Brownell et al. 1996) that a histone acetyltransferase from Tetrahymena was homologous to the yeast transcriptional regulatory protein Gcn5, providing direct evidence that histone acetylation was connected to control of gene expression. Complementary evidence came from a study showing that a mammalian histone deacetylase was related to the yeast repressive transcriptional regulator Rpd3p (Taunton et al. 1996). Since then there has been an explosion in the discovery of histone modifications, as well as a reevaluation of the roles of those that were known previously.

    So before you say my professors would agree with you, DNA_Jock, and Rumraket, you might actually want to comb through the chapters of my textbook. 🙂

    Consider this passage where the words are those I’ve used at TSZ in association with epigenetic including words like Polycomb:

    . In addition, the condensed chromatin structure characteristic of centromeres in organisms as diverse as flies and humans has been shown to be transmissible through centromere-associated proteins rather than DNA sequence. In all of these cases, the DNA sequence remains intact, but its capacity for expression is suppressed. This is likely in all cases to be mediated by DNA methylation, histone modification, presence of a histone variant, or all three; in some cases, we already know that to be true. Perhaps the X chromosome, which inspired early ideas about the role of DNA methylation in epigenetic signaling, is the best example of how all of these mechanisms are interrelated and function together to achieve epigenetic regulation. Recent studies show that silencing of the inactive X chromosome involves, in addition to DNA methylation, specific silencing histone modifications, Polycomb group proteins, noncoding RNAs, and histone variants (Lee 2011). All of these are likely to be involved in transmission of the silenced state during cell division.

    finally

    I am grateful to Dr. John Gurdon for illuminating exchanges, comments, and advice. This work was supported by the intramural research program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

    Gurdon was the Nobel laureate with Yamanaka.

  22. Googling 10HDA gets you mostly quack medicine sites. Googling the cause of queen bee development mostly leads to articles refuting royal jelly as the cause.

    Not saying which is correct, but Sal, could you provide a reference that isn’t more than a couple years old?

  24. stcordova,

    The problem with causal chain arguments in things so complex as life is that it leads to chicken and egg paradoxes. It’s a mostly meaningless argument at some point.

    No. In the case of life, the causal chain is cyclic. Chicken-egg problems, such as they are, relate to the origins of the cycle. The Krebs Cycle in operation is not a chicken-egg problem, likewise the cell cycle/differentiation cascades, or more immediate demands for anabolic and catabolic metabolism.

    The basic pattern of genetic control is that an excess or a deficit of a molecule turns transcription on or off. This is the basic model in both prokaryote and eukaryote. In the eukaryote, there is more to do to get to product or silence. The chain has more in it, but its still a chain and the requirement is the same – to upregulate or downregulate transcription. There is no major difference in mechanism.

    Have you now retreated from your ‘histone code’ claim into “…well, it’s all very complex, so who knows really”?

  25. stcordova,

    Why on Earth would you think they would agree with your side given your side said unflattering things of him?

    Seriously. It’s about ‘sides’ now? I’ve never even mentioned the bloke. I would hope they would agree with my ‘side’ if we were right.

  26. stcordova,

    Exactly the criticism I leveled against Henikoff who dismissed histones roles in eukaryotic epigenetics because prokaryotes don’t have them.

    No he didn’t. You are making stuff up. He said that factors analogous to Yamanaka factors occur in prokaryotes, and therefore finds it unlikely that histones are central to their operation.

  27. So before you say my professors would agree with you, DNA_Jock, and Rumraket, you might actually want to comb through the chapters of my textbook.

    I’d actually rather be publicly humiliated. Wouldn’t that be more fun for you too?

    I doubt that I would extract the same message from the textbook that you do. And I might be more inclined to ask pertinent and critical questions, rather than fawn.

  28. stcordova,

    Gurdon was the Nobel laureate with Yamanaka.

    Well, that settles it. No Nobel Laureate was ever wrong about anything.

  29. stcordova,

    Me: As I’ve mentioned before, I suspect if one of your esteemed profs socked up and tried to correct some of your misunderstandings here, you’d be the same with them as you are with Jock, Rumraket and I.

    Sal: The usual condescending litany of “Sal doesn’t understand.”

    That was not saying you don’t understand, it was saying that your willingness to listen is strongly conditioned by your predisposition towards who is talking. It’s an interesting thought experiment.

  30. stcordova,

    See for yourself if Felsenfeld agrees with you.

    OK, I took a look at the chapter. Just after a quote that Sal leaves hanging, we see this:

    Felsenfeld:

    “It should also be noted that although chromatin structure and biochemistry must certainly be involved in the implementation of this program (see Section 5), the system can be modeled entirely in terms of control of gene expression by specific binding of expressed factors to the regulatory regions of relevant genes. “.

    So yeah. Sounds like a dinosaur to me.

  31. And: “Despite these results, the issue of the role of histone modifications in epigenetic processes continues to be a source of confusion. It is clear that although the term “epigenetic modification” is frequently used, a given histone modification occurring at a given site in the genome may not necessarily be part of an epigenetic mechanism, but simply part of a biochemical process such as gene expression or DNA strand breakage repair. “

  32. Allan Miller:

    It’s not about science, it’s about personality. Or in the case of disputes here, about affiliation.

    As far as affiliation, if it means anything to you Allan, I’d rather hang out at the pub with you than Barry Arrington. 🙂

  33. colewd: In the end, carbon, hydrogen, phosphorus, oxygen, nitrogen and sulfur unites us all.

    Yes, all life is fundamentally the same.

  34. Allan Miller:
    stcordova,

    Well, that settles it. No Nobel Laureate was ever wrong about anything.

    Sal never said anything about Gurdon’s opinions. Gurdon was merely cited in the acknowledgments. Sal was just trying to acquire authority at third hand.

  35. For the record, the swipe taken at Felsenfeld (author of the opening chapter of my class text) at Coyne’s blog. It was in the same post about Mukherjee:

    https://whyevolutionistrue.wordpress.com/2016/05/05/the-new-yorker-screws-up-big-time-with-science-researchers-criticize-the-mukherjee-piece-on-epigenetics/

    Geoffrey North, Senior Editor, Current Biology:

    I have observed this phenomenon over more than 30 years now: in the 80s, studies of transcriptional regulation fell into two clear camps, one the biochemists/geneticists, carrying on the work started by Jacob and Monod to show how transcription factors activate and repress genes, and how the basic mechanisms are conserved between prokaryotes and eukaryotes; the other, influenced strongly by structural biologist/chemists such as Gary Felsenfeld (a student of Linus Pauling), investigating “chromatin structure”, identifying features that correlate with gene expression such as hypersensitive sites (I guess this group was inspired by structural biology’s one unambiguous huge success: the DNA double helix and the subsequent molecular biology zeitgeist of biological insights from structure.)

    I always felt the former were inclined to look for conservation of fundamental mechanisms (yay!) and the latter hoping to show a fundamental difference due to chromatin, somehow related to the greater “complexity” (ill-defined term in biology, frankly) of eukaryotes, metazoans in particular. Of course, DNA methylation was known about then, but the phylogenetic distribution has always been a bit puzzling and despite huge efforts over many years I am not sure the real “function”/role has ever become very clear (perhaps it is in the case of mammalian “imprinting”, not sure off hand).

    Things seemed to die down a bit, the “chromatin project” not really getting very far—and then it reared its head again with a vengeance with discoveries about histone modifications and emergence of “epigenetics” as THE buzzword for the transcription/gene regulation field, taking over peoples minds and seemingly leading to a mass loss of memory of the history of the field, and a mass loss of clear perspective on how DNA/histone modifications fit into an over all process of differential gene regulation.

    The real sticking issue, if had to guess: “the basic mechanisms are conserved between prokaryotes and eukaryotes”. I find that hard to defend since prokaryotes don’t have histones nor histone bearing introns or lots of repetitive elements that seem involved in epigenetic transmission.

    Biological evolution mentioned once in passing in Felsenfeld’s work and the word “conserved” not used at all. Felsenfeld highlight’s the difference between bacteria and multicellular creatures. Is that the real issue?

    Felsenfeld:

    For those with a biochemical point of view, a cell was defined by the multiple interdependent biochemical reactions that maintained its identity.
    ….
    the system can be modeled entirely in terms of control of gene expression by specific binding of expressed factors to the regulatory regions of relevant genes.

    That was the biochemical view, the view that Felsenfeld (at least by Geoffry North’s perspective) is not identified with. Felsenfeld immediately provides a counter example to the purely biochemical view — tada, a structural view.

    The extent to which nucleus and cytoplasm each contributed to the transmission of a differentiated state in the developing embryo was of course a matter of intense interest and debate; a self-stabilizing biochemical pathway would presumably have to be maintained through cell division. A second kind of epigenetic transmission was clearly shown in Paramecia and other ciliates, in which the ciliary patterns may vary among individuals and are inherited clonally (Beisson and Sonneborn 1965). Altering the cortical pattern by microsurgery results in transmission of a new pattern to succeeding generations. It has been argued that related mechanisms are at work in metazoans, in which the organization of cellular components is influenced by localized cytoplasmic determinants in a way that can be transmitted during cell division (Grimes and Aufderheide 1991).

    Felsenfeld then list the other epigenetic mechanisms which includes the very things I’ve harped on.

    For example I just mention the RNA Induced Transcription Silencing complex. The RITS complex was publish by Zofall and Grewell in 2004 and Felsenfeld alludes to their later work in 2006:

    Formation of heterochromatin involves the production of RNA transcripts, particularly from repeated sequences, that are processed into small RNAs through the action of proteins such as Dicer, Argonaute, and RNA-dependent RNA polymerase (Zofall and Grewal 2006). These RNAs are subsequently recruited to the homologous DNA sites as part of complexes that will eventually include enzymes that deliver “silencing” histone modifications, thus initiating the formation of heterochromatin.

    I’ve harped on the PRC2 polycomb repression complex and HOTAIR lncRNA at least five times at TSZ in connection with epigenetics. It echoes Felsenfeld’s text:

    example, in the case of HOTAIR (Rinn et al. 2007) and Kcnq1ot1 (Pandey et al. 2008; Mohammad et al. 2010), the RNAs tend to associate with DNA fairly near their own sites of synthesis, and bring with them the histone modifying Polycomb complex PRC2 (see below), bound to a specific sequence on each RNA.

    I chromatin remodeling complexes and even specifically SWI/SNF in another thread where I mentioned the Vitamin D receptor, and SWI complex is shown in a diagram above:

    Activation was accompanied by repositioning of nucleosomes, and it was suggested that this was the critical event in making the promoter accessible. A fuller understanding of the significance of these findings required the identification of ATP-dependent nucleosome remodeling complexes such as SWI/SNF and NURF

    It’s not like I’ve been saying stuff on epigenetics that is far away from the things in Feslenfeld’s text. I think I’ve been pretty faithful to the program of learning that he basically mapped out in that over view, and I’ve recited a lot of things at TSZ about epigenetic according to the structure of his essay.

  36. Sal, are you going to get back to me on how epigenetic changes spread in a population, or perhaps get back to me on the royal jelly thing?

  37. stcordova,

    if it means anything to you Allan, I’d rather hang out at the pub with you than Barry Arrington

    Cheers! 🙂

  39. stcordova,

    For the record, the swipe taken at Felsenfeld (author of the opening chapter of my class text) at Coyne’s blog. It was in the same post about Mukherjee:

    I don’t read it as a swipe at him particularly – he’s an example of the structural biology camp, and people are skeptical of some of its wilder claims. But it is clear from the passages I abstracted above that Felsenfeld is more of a traditionalist than you seem to think he is.

  40. stcordova,

    The real sticking issue, if had to guess: “the basic mechanisms are conserved between prokaryotes and eukaryotes”. I find that hard to defend since prokaryotes don’t have histones nor histone bearing introns or lots of repetitive elements that seem involved in epigenetic transmission.

    But the basic mechanisms are conserved. On histones, it’s like saying sex became completely different when people started wearing pants.

  42. As far as this whole thing about Transcription Factors being primary, the problem is that in network topologies like the internet and gene regulatory networks, there is decentralization rather than centralization of control.

    That’s not an analogy.

    On histones, it’s like saying sex became completely different when people started wearing pants.

    THAT’s an analogy.

    </Crocodile Dundee>
    LMAO

  43. DNA_Jock: On histones, it’s like saying sex became completely different when people started wearing pants.

    THAT’s an analogy.

    Does how good the analogy is depend on if whether they’re wearing the pants DURING sex?

  46. Until Sal addresses ho a Designer would design the Thompson circuit, he’s just building a case for evolution.

    Not that there’s anything wrong with that.

    I’m still waiting to see how epigenetic changes wormhole their way into populations as heritable elements. That was the number one objection to the New Yorker article.

    And while he’s at it, a few remarks on royal jelly that don’t come from quack food supplement commercials.

  47. Allan Miller:

    But the basic mechanisms are conserved. On histones, it’s like saying sex became completely different when people started wearing pants.

    As North commented (his opinion):

    I always felt the former [biochemists/geneticists like Monod] were inclined to look for conservation of fundamental mechanisms (yay!) and the latter [like structural biologists/chemists like Felsenfeld] hoping to show a fundamental difference due to chromatin

    Non-conservationists would seem to be naturally favored by creationists and less by evolutionists.

    The course description of my Biochemistry Class clearly reflects Felsenfeld’s influence on the structure of the course, it follows the structure of his essay:

    Biological Importance of Modifications in DNA and Chromatin

    Chromatin modifications play important roles in many cellular processes including the regulation of gene expression, DNA repair, and the
    heterochromatin formation. This course will explore the various biological roles chromatin modifications play in eukaryotic cells. Topics that will be
    discussed include: histone and DNA modifications and the enzymes responsible for these modifications; mechanisms of chromatin remodeling and
    transcription regulation; the role of non-coding RNAs in chromatin structure and gene regulation; higher-order chromatin organization and the use of
    various chromosome capture conformation methods; and, chromatin structure and DNA damage repair. In addition, this course will introduce students to
    the genome-wide analysis of ChIP-seq and RNA-seq data using the Galaxy and UCSC web servers and other bioinformatics software tools.

    Learning objectives:
    Understand the basic concepts behind epigenetics
    Understand why epigenetics is important to understanding human diseases
    Explain how epigenetic mechanisms work.

    The perspective taught on gene-regulation and epigenetics is Chromatin-modification centric, not transcription factor centric (the “dinosaur view”).

    Multicellular creatures have unique requirements of epigenetic transmission in cell lines from zygote to adult which is not an issue at all for unicellular creatures. So epigenetics is a far more meaningful and significant term for multicellular creatures than unicellular.

    Felsenfeld points out the difficulty of transcription factors being able to pass epigenetic information from one cell to another:

    It has been proposed that the definition of an epigenetic mechanism should include, in addition to the property of being maintained through cell division, a requirement for an initial signal, such as expression of a transcription factor, that is not needed once the new state is established (Berger et al. 2009). Behavior of this kind has been described for the glucocorticoid response element in which transient binding of glucocorticoid receptor (GR) to some sites leads to nucleosome remodeling that makes it possible for a modified estrogen receptor molecule to bind after the GR has departed (Voss et al. 2011). It should be kept in mind that most eukaryotic transcription factors do not have long residence times at their binding sites, but turn over rapidly. Certain kinds of chromatin modifications could, in principle, provide a mechanism to integrate signals from multiple transcription factors (Struhl 1999).

    Now as this relates to the hated New Yorker article, note the name, “Berger”. That is none other than the Shelly Berger mentioned in the New Yorker article, and Felsenfeld defers to her Chromatin-centric rather than Transcription-factor centric view of epigenetics. The 2009 paper Berger which Felsenfeld references has this to say:

    A recent meeting (December 2008) regarding chromatin-based epigenetics was hosted by the Banbury Conference Center and Cold Spring Harbor Laboratory. The intent was to discuss aspects of epigenetic control of genomic function, and to arrive at a consensus definition of “epigenetics” to be considered by the broader community. It was evident that multiple mechanistic steps lead to the stable heritance of the epigenetic phenotype. Below we provide our view and interpretation of the proceedings at the meeting.
    …
    Definition: “An epigenetic trait is a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence.”

    So now it is becoming clearer why this fight over the New Yorker article breaking out. The chromratin-centric camp (which the creationists will naturally side with since it tends to argue punctuated novelty between life forms) vs. the transcription-factor centric camp (which the evolutionist will lean toward transcription-factor centrism since it argues conserved continuous universal mechanism across all life forms and thus creates less problems for evolution).

    Allan Miller:

    But the basic mechanisms are conserved. On histones, it’s like saying sex became completely different when people started wearing pants.

    Unicellular Prokaryotic “sex” (gene transfer, plasmid transfer, whatever) is completely different than multicellular eukaryotic sex.

    Anyway, now it’s becoming clearer why all those people came forward (as reported by Coyne) to argue on an obscure article. From Coyne’s blog, the transcription-factor centrists show their colors against the chromatin-centrists:

    First among them is Coyne himself

    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.

    and then Henikoff:

    Mukherjee seemed not to realize that transcription factors occupy the top of the hierarchy of epigenetic information, that this has been widely accepted in the broader chromatin field, and that histone modifications at most act as cogs in the machinery that enforces the often complex programs specified by the binding of transcription factors. — Henikoff

    Well, that doesn’t exactly agree with Shelley Berger’s group (praised in the New Yorker article) who used the phrase “chromatin based epigenetics.” Henikoff doesn’t even acknowledge there is the “chromatin based epigenetics” camp and pretends the “transcription factor” epigenetics camp is the dominant view rather than conceding it’s becoming the dinosaur view.

  49. You might answer my earlier question about control of the cascade. Deacetylation does not happen by accident. So what (if not the TF) opens the door so that the TF can bind?

    For the record, though I’ve studied under the tutelage of the chromatin-centrists, I don’t think there is centralized control therefore I’m a bit of relativist/Copernican when it comes to control — I argue for some level of decentralization (BITCOIN nodes is an example of decentralized entity that is organized toward a goal).

    The cytoplasmic-centrists and glycome-centrists have yet to show up. I think a lot of epigenetic control is in the cytoplasm and glycome. There is far too much we don’t know. It’s premature to be making pronouncements about things we have no knowledge of.

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