356 thoughts on “Epigenetic Memory Changes during Embryogenesis”

1. Frankie,

   The first question I raised was how did Tom know the movements were random. I then added the part of what a transposon is.

   The point I was responding to was about origins. Your immediate follow-on point – to me directly, in response to the point about origins – was about action. Easy to click back through the link trail to verify this. What you may or may not have said to Tom is irrelevant.

   As far as our exchange is concerned, you switched from origin (‘how did that [enzyme encoding] arise by stochastic processes?’) to action (‘OK so you don’t have any justification for calling the actions of transposons random’). That was your response to me, not to Tom, a question that I had not, prior to that statement, been invited to address.

   And you don’t have any justification for calling their movements random

   Is anything random in your view? Give an example of something you consider random, and how it is different from something which you reckon isn’t. It is a word with numerous potential meanings.

2. Allan Miller,

   LoL! So you can’t support the claim. That is all you had to say.

   Point mutations appear to be happenstance occurrences.

3. Frankie,

   LoL! So you can’t support the claim. That is all you had to say.

   Fucksake! You asked a different fucking question first! One about the enzymes involved in transposition.

   I am now proceeding to deal with the completely different question, the randomness of transposition itself, for which I need to know WHAT YOU MEAN BY RANDOM …

   Point mutations appear to be happenstance occurrences.

   So you think point mutations are random? How did you determine that? How do you go about supporting the claim that something is ‘random’ (assuming ‘happenstance occurrence’ is your preferred definition)?

4. Allan Miller: Is anything random in your view? Give an example of something you consider random, and how it is different from something which you reckon isn’t. It is a word with numerous potential meanings.

   I think we tend to think of something as random when it conforms to a certain probability distribution. An OP on randomness could be interesting. It would probably evolve into a discussion of causes.

   What caused that particular distribution? If we can’t say, does that mean it has no cause? If all that materialism had was an appeal to randomness, would anyone choose it over ID?

5. Mung: I think we tend to think of something as random when it conforms to a certain probability distribution. An OP on randomness could be interesting.

   I’d like that post too. Perhaps a discussion of parametric vs nonparamentric methods also.

6. Mung: I think we tend to think of something as random when it conforms to a certain probability distribution.

   How do you measure the probability distribution.

   By most measures, the digits in pi are indistinguishable from random.

   Your definition is not what we mean by random when discussing mutation.

7. Mung,

   I think we tend to think of something as random when it conforms to a certain probability distribution.

   Well, change that to a certain probability distribution and you have the mathematical definition (nothing is certain in probability, haha). But people often mean – uh – ‘undirected’ …

   An OP on randomness could be interesting.

   Go for it! I once spent several weeks arguing on the wrong side vis a vis the role of randomness in evolution. Boy was my face red.

   It would probably evolve into a discussion of causes.

   What caused that particular distribution? If we can’t say, does that mean it has no cause?

   Not necessarily.

   If all that materialism had was an appeal to randomness, would anyone choose it over ID?

   Why would someone appeal to a probability distribution? And intelligence can still act probabilistically. I don’t see that choice.

8. Apologies for the sporadic responses. I’m at the NIH grad school 2 evenings a week and the other evenings are spent trying to digest through the professors’ assignments!

   As far as epigenetics is concerned, I’ve given verbatim definitions from the researchers themselves. They provide lectures right from the same buildings where their laboratories are — where they research epigenetics and non-coding RNAs! The diagram in the OP is from a class lecture.

   So far I am convinced you are incoherent. I challenge you to prove me wrong. My challenge should not be too difficult given it can be answered by high school students.

   I’m sorry Tom, such high school taunts are inappropriate for a discussion of biochemistry. You’re the one being incoherent about the present usage of the term “epigenetic”. If one simply googles “epigenetic marks” and looks for images and diagrams, one will get a diagram like the following which is pretty much what I’ve been saying for the last 2 months at TSZ, what I’ve gotten in NIH grad school classed and what I’ve gotten attending conferences like ENCODE 2015. What I’ve provided is textbook.

   In contrast. what you’ve provided isn’t even suitable for high school because it is simply wrong. See this diagram below, it relates to the picture in the OP, and it should correct such unbelievably incoherent declarations like the one you made such as

   DNA methylation & Histone acetylation clearly are a result of “epigenetic memory

   — TomMeuller

   Note what the diagram says:

   DNA methylation – Methyl group…can tag DNA and activate or repress genes

   Histone modification — the binding of epigenetic factors to histone “tails” alters the extent to which DNA is wrapped around histones and the availability of genes in the DNA to be activated

   I put an ellipsis since the reference to dietary sources muddles the basic issue.

   https://upload.wikimedia.org/wikipedia/commons/d/dd/Epigenetic_mechanisms.jpg

9. Now a topic from last night’s lecture, and relevant to importance of epigenetic influence on genes:

   http://learn.genetics.utah.edu/content/epigenetics/imprinting/

   http://learn.genetics.utah.edu/content/epigenetics/imprinting/

   For most genes, we inherit two working copies — one from mom and one from dad. But with imprinted genes, we inherit only one working copy. Depending on the gene, either the copy from mom or the copy from dad is epigenetically silenced. Silencing usually happens through the addition of methyl groups during egg or sperm formation.

   The epigenetic tags on imprinted genes usually stay put for the life of the organism. But they are reset during egg and sperm formation. Regardless of whether they came from mom or dad, certain genes are always silenced in the egg, and others are always silenced in the sperm.

   Current estimates are that 1-2% of human genes are epigenetically silenced (imprinted) on either the paternal or maternal side.

10. Now look again at the diagram in the OP, notice how in the first few hours the epigenetic marks are removed from the paternal (sperm) DNA in the picture in block C at 3 hours after fertilization and then new ones are put in at 8 hours after fertilization in block I.

    Persumably this depicts the time around whic imprinting may occur. Now where is the information stored to make the imprinting happen since it isn’t obviously stored in the erased memory of the paternal DNA? Hmm??? I can think of only one or two places — the non-Coding RNA or the cytoplasm or both! 🙂 This is proof yet again that DNA does not contain all the information or technology to make life.

11. A picture is worth a thousand words.
    http://learn.genetics.utah.edu/content/epigenetics/imprinting/

12. stcordova,

    Gender-based imprinting cannot last more than one generation, pretty much by definition – there is only one opportunity to have a binary pattern with a diploid cell formed from two incoming complementary haploids.

    Since methylation is done by proteins which are made via DNA, and the genes methylated are coding genes not junk, I’m not sure why this is a big deal.

13. Allan:

    Gender-based imprinting cannot last more than one generation, pretty much by definition

    I don’t think that is correct, it is persistent, otherwise in some cases there is bad consequence or even death:

    http://www.nature.com/scitable/topicpage/Genomic-Imprinting-and-Patterns-of-Disease-Inheritance-899

    Cancer

    A simple diagram of lines and circles shows how expression of the genes IGF2 and H19 influence cell growth. In normal cells, IGF2 expression on paternal chromosomes leads to cell growth, whereas H19 expression on maternal chromosomes reduces cell growth. However, in individuals with Wilms’ tumor, IGF2 expression is also turned on on the maternal chromosome, leading to loss of imprinting, abnormal cell growth, and tumor formation.

    Figure 1: Model of loss of imprinting of IGF2, H19 and methylation of the H19 promoter in Wilms’ tumor.

    In normal cells, the paternal IGF2 and maternal H19 genes are expressed (shown large). Several sites upstream of H19 are methylated on the paternal allele (filled circles) and unmethylated on the maternal allele (open circles). In tumors with LOI, the maternal chromosome reverses to a paternal epigenotype, with a paternal pattern of methylation of the H19 promoter, IGF2 turned on, and H19 turned off, causing increased cell growth. LOI of H19 on the maternal chromosome, when it occurs, could occur independently or could be influenced by events in the paternal chromosome.

    © 1994 Nature Publishing Group Steenman, M. et al. Loss of imprinting of IGF2 is linked to reduced expression and abnormal methylation of H19 in Wilms’ tumor. Nature Genetics 7, 437 (1994). All rights reserved. View Terms of Use

    Figure Detail

    In addition to these syndromes, imprinting has been linked to certain cancers. For instance, Wilms’ tumor is a type of embryonic kidney cancer that is associated with the IGF2/H19 locus on chromosome 11. H19 is a noncoding RNA of unknown function with properties that can suppress growth. IGF2 codes for insulin-like growth factor 2, a growth factor highly expressed in many types of tumors. These two genes are both imprinted, and normally, only the maternal copy of H19 and the paternal copy of IGF2 are expressed (Steenman et al., 1994). In cancer cells, however, both H19 and IGF2 typically lose their imprinting (Moulton et al., 1994; Steenman et al., 1994). Scientists hypothesize that if the function of H19 is to turn off IGF2 expression, then the loss of H19 expression could result in overexpression of IGF2, thus leading to tumorigenesis (Steenman et al., 1994).

    Research has helped support this conclusion, as Wilms’ tumor cells have shown loss of imprinting of the maternal chromosome and a switch to the paternal pattern of methylation (Steenman et al., 1994). Moreover, Thomas Moulton and colleagues showed that H19 mRNA expression was decreased at least twentyfold in most Wilms’ tumors, indicating that H19 is inactivated in tumor cells (Moulton et al., 1994). This results in the overexpression of IGF2 and reduced expression of H19. Because H19 functions to slow cell growth and IGF2 stimulates cell growth, loss of imprinting at the H19/IGF2 locus results in uncontrolled cell growth that can lead to tumor formation (Figure 1; Steenman et al., 1994).

    Loss of imprinting (i.e., the loss of normal allele-specific gene expression) can also result in cancer when an imprinted, normally silent allele that provides cells with a growth advantage is activated, resulting in uncontrolled cell growth and division. For example, along with Wilms’ tumor, loss of imprinting of the IGF2 gene is associated with many other types of cancer, including lung, colon, and ovarian tumors (Robertson, 2005). Cancers can also form in cases in which a tumor suppressor gene is imprinted, and the single expressed copy of the tumor suppressor is mutated or loses its function (Jirtle & Weidman, 2007).

14. stcordova,

    I don’t think that is correct, it is persistent, otherwise in some cases there is bad consequence or even death:

    It is persistent during the generation, sure. But I meant one organismal generation, not one cellular generation. A zygote inherits parentally and maternally imprinted chromosomes. But then, at the next generation, its gamete imprinting pattern passed on is that based on its own gender, not either of its inherited imprinting patterns from mom and pop.

    In a diploid with two genders, you couldn’t possibly have stable gender-related imprints over multiple organismal generations. They are generated afresh.

15. Also regarding heritable of epigenetic marks on the maternal or paternal side only:

    http://www.ncbi.nlm.nih.gov/pubmed/21092170

    Abstract

    BACKGROUND:

    Genomic imprinting is an evolutionary conserved mechanism of epigenetic gene regulation in placental mammals that results in silencing of one of the parental alleles. In order to decipher interactions between allele-specific DNA methylation of imprinted genes and evolutionary conservation, we performed a genome-wide comparative investigation of genomic sequences and highly conserved elements of imprinted genes in human and mouse.

    RESULTS:

    Evolutionarily conserved elements in imprinted regions differ from those associated with autosomal genes in various ways. Whereas for maternally expressed genes strong divergence of protein-encoding sequences is most prominent, paternally expressed genes exhibit substantial conservation of coding and noncoding sequences. Conserved elements in imprinted regions are marked by enrichment of CpG dinucleotides and low (TpG+CpA)/(2·CpG) ratios indicate reduced CpG deamination. Interestingly, paternally and maternally expressed genes can be distinguished by differences in G+C and CpG contents that might be associated with unusual epigenetic features. Especially noncoding conserved elements of paternally expressed genes are exceptionally G+C and CpG rich. In addition, we confirmed a frequent occurrence of intronic CpG islands and observed a decelerated degeneration of ancient LINE-1 repeats. We also found a moderate enrichment of YY1 and CTCF binding sites in imprinted regions and identified several short sequence motifs in highly conserved elements that might act as additional regulatory elements.

    CONCLUSIONS:

    We discovered several novel conserved DNA features that might be related to allele-specific DNA methylation. Our results hint at reduced CpG deamination rates in imprinted regions, which affects mostly noncoding conserved elements of paternally expressed genes. Pronounced differences between maternally and paternally expressed genes imply specific modes of evolution as a result of differences in epigenetic features and a special response to selective pressure. In addition, our data support the potential role of intronic CpG islands as epigenetic key regulatory elements and suggest that evolutionary conserved LINE-1 elements fulfill regulatory functions in imprinted regions.

    My opinion only — “evolutionary conserved” should be euphemism for “God-made similarity”. Either notion will yield the same operational results in experiment and analysis. “God-made-similarity” might even be a better conception since it may lead to more reverence for using the patterns of similarity and diversity for decoding function rather than looking at the patterns as the result of selection acting on random noise.

16. Allan:

    In a diploid with two genders, you couldn’t possibly have stable gender-related imprints over multiple organismal generations. They are generated afresh.

    I’m suspect that is incorrect. One of us is wrong.

    I’m taking 2 classes at the NIH right now and taught by a pool of 8 instructors, and one of them is an imprinted gene specialist. This discussion is helpful as it helps me review what I’m learning and to test my command of the subject matter.

    If an imprinted gene is conserved, it would seem to me the epigenetic marks of the imprinting are heritable. Furthermore, especially for the paternal side where the imprints are erased in the first three hours after fertilization and then re-written (dare I say rebooted) 5 hours later, it is apparent the information to do this is neither in the DNA nor the methylation marks but must reside in the ncRNAs, the information bearing glyco-protein complexes, or who knows where!

    I asked the professor where the imprinting information is stored during the erasure process in the first 3 hours after fertilization and he indicated know one knows!!!! It is a topic of future research.

17. stcordova,

    My opinion only — “evolutionary conserved” should be euphemism for “God-made similarity”. Either notion will yield the same operational results in experiment and analysis.

    Only if you look sideways at what the evolutionary assumers are saying and copy their every move! Evolution provides an explanation for changes in methylation pattern and CG richness – two biochemically associated parameters whose inherent biases would be expected to be compounded over evolutionary time. ‘God’ does not – there is no apparent functional reason for the pattern; it is sufficiently explained by different biochemical pressures. One can hope for a less incidental, more functional reason, as you do with everything else in the genome, but that is hardly following the evidence.

    Invoking God simply says “whatever we see – that’s what God would be expected to do”. It explains everything and nothing.

18. stcordova,

    I’m suspect that is incorrect. One of us is wrong.

    Yep – you! 😉 It’s right there in the ‘picture that’s worth a thousand words’ upthread.

19. stcordova,

    If an imprinted gene is conserved, it would seem to me the epigenetic marks of the imprinting are heritable.

    The two things are not intimately related. If a gene is conserved, that relates to its sequence, not a parallel persistence for any epigenetic modifications to the bases. The capacity to support methylation is a source of constraint, not the physical fact of being methylated.

    Furthermore, especially for the paternal side where the imprints are erased in the first three hours after fertilization and then re-written (dare I say rebooted) 5 hours later, it is apparent the information to do this is neither in the DNA nor the methylation marks but must reside in the ncRNAs, the information bearing glyco-protein complexes, or who knows where!

    It’s not ‘apparent’ at all. There is nothing to stop a protein being responsible for wiping epigenetic marks, and hence being sourced from DNA. (Equally, of course, where do you think ncRNAs come from?)

    I asked the professor where the imprinting information is stored during the erasure process in the first 3 hours after fertilization and he indicated know one knows!!!! It is a topic of future research.

    I will buy you a beer if it is ever discovered that erasure results from anything other than a DNA-sourced component.

20. The obvious place to store epigenetic gender marking for both erasure and rewrite (and, indeed, X inactivation) is on the chromosome itself, or its chromatin. Storing it ‘in the cytoplasm’ seems like a clunky and error-prone way to do it.

21. And, the obvious way to achieve a particular consistent imprint on a particular chromosome is to simply have it written anew, by the same enzyme that did it last time, rather than the implicit idea that it is read off, stored somewhere temporarily and then reapplied.

22. stcordova,

    Sal

    I suspected your initial answer was incoherent. Now I am convinced you do not understand epigenetics!

    I asked you to explain what was remembered and how. You provided a patchwork quilt of cut & pasted references that did not answer my question at all. A high school student would have received a failing grade for such a travesty!

    Here is where you failed. Your series of answers of March 21 did not answer my specific question:

    As you now realize (if you understand your own posts), nucleosome modifications are by themselves not self-perpetuating and must therefore be considered peripheral to the epigenetic story. DNA methylation & Histone acetylation clearly are a result of “epigenetic memory” and not a cause.

    You were specifically asked …to explain the difference between a mule and a hinny, where a female hinny zygote is a diploid cell with two sets of chromosomes: one set from a donkey and another set from a horse; which BTW describes the exact same scenario for the female mule zygote. Those differential nucleosome modifications you keep on going on about, should be identical in both zygote scenarios, yet hinnies and mules are quite different due to “epigenetics”.

    Your answer failed to make any mention of hinnys and mules!

    I note that you are eventually getting closer to the mark by March 23! To your credit you are learning, even if I fault you for making up untenable theses on the fly and you seem to ignore the fact that your 12:12 AM post is contradicting your earlier 11:44 & 11:51 posts.

    Bravo, you have stumbled across the excellent… http://learn.genetics.utah.edu/content/epigenetics/imprinting/
    …site which does address my question at a high school level.

    I am bemused that you fail to see how this site’s explanation constitutes a complete and total validation of Mark Ptashne’s thesis which you earlier dismissed as

    Sal:Ptashne is old school obsolete.

    LOL! Seriously?! You really don’t get it?!

    Ptashne nailed it! With a tip of the hat to Allan Miller, Classical Geneticists have known for decades that there exist gene regulatory models where Positive Feedback control in fact maintains homeostasis, if by homeostasis we understand “status quo”! The maintenance of one “status quo” over another could be deemed your “memory” …of sorts. It gets better: irreversible commitment points often occur in Biology. Self-perpetuating responses are then required long after the triggering stimulus is removed and these responses occur as a result of positive feedback as well as double-negative feedback mechanisms as first described by Jacob and Monod.

    http://tinyurl.com/pqx4jom

    A fellow Canadian James Ferrell does an excellent job of elucidating these difficult concepts.

    http://www.medicine.mcgill.ca/physio/mackeylab/courses_mackey/pdf_files/ferrell_2002.pdf

    What I find more amazing is that you have actually stumbled across the important part of the answer to my original question about hinnies and mules and you failed to recognize it.

23. I’m suspect that is incorrect. One of us is wrong.

    Yep – you! 😉

    No, not me. 🙂

    https://en.wikipedia.org/wiki/Transgenerational_epigenetic_inheritance

    Transgenerational epigenetic inheritance is the transmittance of information from one generation of an organism to the next (e.g., parent–child transmittance) that affects the traits of offspring without alteration of the primary structure of DNA (i.e., the sequence of nucleotide
    ….

    And 3 examples of transgeneration epigenetic inheritance, note the 1st example.

    https://www.episona.com/3-examples-transgenerational-epigenetic-inheritance/

    1. Parental allele-specific imprinting

    There are a small subset of genes called imprint genes. Normally, we have two functional copies (i.e., alleles) of each gene – one from our mother and one from our father. For imprinted genes, either the maternal or paternal allele is methylated significantly such that only one copy produces protein. For reasons that still remain to be elucidated, this is critical; particularly for early development (e.g., embryogenesis). The vast majority of imprinted genes are involved in controlling embryo growth and development, including development of the placenta.

    Poor embryogenesis and male infertility. Over the last few decades, numerous scientific studies have tried to understand the mechanisms behind male infertility. However, more than 50% of male factor infertility cases still have no known cause. Until very recently, people mostly thought sperm was simply delivering DNA to the egg. As the old saying goes, men just need to show up. Our increasing understanding of epigenetics has completely turned this view on its head. Numerous studies have found abnormal methylation of specific imprint genes of sperm are highly correlated to male infertility. This is precisely why Episona is investigating imprint genes in sperm to understand how aberrant methylation at these loci might be contributing to male infertility (i.e., poor embryogenesis after conception). You can find good reviews of the data by Douglas Carrell, Celine Boissonnas, and Singh Rajender. If you would like to receive copies of some of the scientific manuscripts, please feel free to contact us.

    Fetal development and imprint disorders. It is also thought that proper epigenetic inheritance of genomic imprinting is critical for later development as well. Particularly, some of the imprint genes seem to be important for early brain development and, when not properly methylated, can leads to diseases such as Prader-Willi syndrome, Beckwith-Wiedermann syndrome, Silver-Russell syndrome, and Angelman syndrome. It is also thought these genes are involved with growth more broadly. Below is an excellent interview from EpiGenie with Dr. Gudrun Moore, who is studying the epigenetics of growth and early development at University College London.

24. TomMeuller:

    Sal

    I suspected your initial answer was incoherent. Now I am convinced you do not understand epigenetics!

    So what part of this definition do you disagree with, from the publishers of the prestigious scientific journal nature:

    http://www.nature.com/scitable/topicpage/Epigenetic-Influences-and-Disease-895

    What Is Epigenetics? How Do Epigenetic Changes Affect Genes?

    Epigenetics involves genetic control by factors other than an individual’s DNA sequence. Epigenetic changes can switch genes on or off and determine which proteins are transcribed.

    This triangle-shaped diagram shows that three systems can interact to silence genes in cells. Arranged as points on the triangle, the systems are DNA methylation, histone modification, and RNA. From each of the systems, arrows point to the interior of the triangle, indicating that these systems may produce heritable silencing, though RNA-associated silencing in higher organisms has not yet been established.

    DNA Methylation
    ….

    DNA methylation is a chemical process that adds a methyl group to DNA. It is highly specific and always happens in a region in which a cytosine nucleotide is located next to a guanine nucleotide that is linked by a phosphate; this is called a CpG site (Egger et al., 2004; Jones & Baylin, 2002; Robertson, 2002). CpG sites are methylated by one of three enzymes called DNA methyltransferases (DNMTs) (Egger et al., 2004; Robertson, 2002). Inserting methyl groups changes the appearance and structure of DNA, modifying a gene’s interactions with the machinery within a cell’s nucleus that is needed for transcription. DNA methylation is used in some genes to differentiate which gene copy is inherited from the father and which gene copy is inherited from the mother, a phenomenon known as imprinting.

    Histone Modifications

    Histones are proteins that are the primary components of chromatin, which is the complex of DNA and proteins that makes up chromosomes. Histones act as a spool around which DNA can wind. When histones are modified after they are translated into protein (i.e., post-translation modification), they can influence how chromatin is arranged, which, in turn, can determine whether the associated chromosomal DNA will be transcribed. If chromatin is not in a compact form, it is active, and the associated DNA can be transcribed. Conversely, if chromatin is condensed (creating a complex called heterochromatin), then it is inactive, and DNA transcription does not occur.

    There are two main ways histones can be modified: acetylation and methylation. These are chemical processes that add either an acetyl or methyl group, respectively, to the amino acid lysine that is located in the histone. Acetylation is usually associated with active chromatin, while deacetylation is generally associated with heterochromatin. On the other hand, histone methylation can be a marker for both active and inactive regions of chromatin. For example, methylation of a particular lysine (K9) on a specific histone (H3) that marks silent DNA is widely distributed throughout heterochromatin. This is the type of epigenetic change that is responsible for the inactivated X chromosome of females. In contrast, methylation of a different lysine (K4) on the same histone (H3) is a marker for active genes (Egger et al., 2004).

    RNA-Associated Silencing

    Genes can also be turned off by RNA when it is in the form of antisense transcripts, noncoding RNAs, or RNA interference. RNA might affect gene expression by causing heterochromatin to form, or by triggering histone modifications and DNA methylation (Egger et al., 2004).

    Contrast this with this babble:

    Your answer must somehow explain, what is being remembered and how. Understand that your answer CANNOT make reference to DNA methylation nor Histone acetylation because as Mark Ptashne explained, nucleosome modifications are by themselves not self-perpetuating and must therefore be considered peripheral to the epigenetic story. — TomMeuller

    Gee, Tom, that blurb from the nature website doesn’t say the DNA Methylation,Histone Modificaiton are peripheral to epigenetics — they’re rather central.

    You want to go ahead an promote your idiosyncratic definitions, you’re welcome to do so, but don’t take my usage of standard definitions versus your idiosyncratic usuage as evidence of incoherence on my part. Rather, it’s evidence of your idiosyncratic redefinition of modern day textbook definitions of epigenetics.

    I once said a while back, I could probably post textbook stuff on the net, and just because I’m a creationist, the anti-ID crowd would find a way to disagree with it even if it was mainstream literature. You’re proving my point.

25. Allan Miller:
    The obvious place to store epigenetic gender marking for both erasure and rewrite (and, indeed, X inactivation) is on the chromosome itself, or its chromatin. Storing it ‘in the cytoplasm’ seems like a clunky and error-prone way to do it.

    Hi Allan

    To quote Ptashne:

    it is patently incorrect to :

    “… refer to nucleosome modifiers as “epigenetic”—they, like the very many proteins recruited to genes by specific transcription regulators, are parts of a response, not a cause, and there is no convincing evidence they are self-perpetuating.” Mark Ptashne

    So how does Epigenetics happen?

    Again to Mark Ptashne:

    “The answer—where we know it—is positive feedback, a process understood for years for bacterial regulatory systems.”

    I direct everyone’s attention to PZ Myers’ great cancer series that directly contradicts many current over-simplifications of Epigenetics that often consitutes textbook dogma.

    http://scienceblogs.com/pharyngula/2013/10/12/micrornas-and-cancer

    Myers picks up where Ptashne left off – without continual recruitment of transcription factors, nucleosome modifications will inexorably decay. That is what makes epigenetics “epi” in the sense of “nearly” or “not quite” irrevokable inheritance in the classical sense of genetics as William Bateson first imagined.

    To understand epigenetics, we need first to understand the cytoplasmic transcription factors (and other regulatory elements) that maintain epigenetic memory and how this memory fades as transcription factors and other regulatory elements can dilute.

    One key candidate mentioned by Ptashne and examined in great detail by Myers would be miRNAs.

    Focusing on your contention:

    I refer you to caynazzo’s responses to my earlier naive questions

    http://tinyurl.com/jr9mh78
    http://tinyurl.com/z2u2qvw

    My very last answer to caynazzo’s second answer represents a cyber version of me banging my head against a cyber wall. It would appear that Ptashne is vindicated by the observation that “Some sort of trans-factors interact with the allele discriminating signal…” during imprinting.

    Although, rereading that particular sandwalk.blogspot thread, still leaves me scratching my head. There may could be a way to rescue the primacy of differential DNA architecture, maybe even nucleosome modification, but not at all along the lines stcordova suggests… bringing us back to your original contention.

    hmmm… your thoughts?

26. AllanMiller:

    If a gene is conserved, that relates to its sequence, not a parallel persistence for any epigenetic modifications to the bases. The capacity to support methylation is a source of constraint, not the physical fact of being methylated.

    No not only DNA is conserved but some methylation patterns. Methylation patterns can also be conserved and inherited:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4255770/

    DNA methylation in the genome plays a fundamental role in the regulation of gene expression and is widespread in the genome of eukaryotic species. For example, in higher vertebrates, there is a “global” methylation pattern involving complete methylation of CpG sites genome-wide, except in promoter regions that are typically enriched for CpG dinucleotides, or so called “CpG islands.” Here, we comprehensively examined and compared the distribution of CpG sites within ten model eukaryotic species and linked the observed patterns to the role of DNA methylation in controlling gene transcription. The analysis revealed two distinct but conserved methylation patterns for gene promoters in human and mouse genomes, involving genes with distinct distributions of promoter CpGs and gene expression patterns. Comparative analysis with four other higher vertebrates revealed that the primary regulatory role of the DNA methylation system is highly conserved in higher vertebrates.
    ….
    The whole-genome DNA methylation data for 17 mouse tissues were obtained using whole-genome bisulfite sequencing (bisulfite-seq) using the Illumina Hiseq2000 platform.

    I’m providing textbook, mainstream literature evidence that some epigenetic modifications are inherited.

    Clearly some epigenetic patterns change during development as evidenced by the photo in the OP, but some of the epigenetic marks must persist transgenerationally.

    Some epigenetic marks clearly change such as the marks on Chromosome 17 of two twins women:

    http://corporatepress.com/clientfiles/faseb/56811/images/HorizonsInBioscience-Chromosome17-522×350.png

27. stcordova,

    Sal – if you persist in cutting and pasting huge blocks of other people’s thinking, you are not demonstrating understanding and you are wasting both our time.

    Please respond to me no more – until you answer my specific question about hinnies and mules.

    Failing that – I will have no option but to invoke the neat “ignore” function.

28. stcordova,

    Sal – let’s see if I can help you with answering the question.
    You like this site – check out this particular link:
    http://learn.genetics.utah.edu/content/epigenetics/epi_learns/

    Now think about the hinny/mule problem and the important detail that nucleosome modifications are parts of a response, not a cause… and alone are not self-perpetuating. The very last diagram on the page is a little misleading on that particular score.

    That is the part you don’t seem to get.

29. Sal – if you persist in cutting and pasting huge blocks of other people’s thinking, you are not demonstrating understanding and you are wasting both our time.

    I’m demonstrating your lack of understanding by cutting and pasting what you should already understand. I’m just driving home the point to readers of this thread how far out in left field your idiosyncratic non-standard usage of the term “epigenetics” is.

    Maybe you can actually read mainstream literature on epigenetics from these clippings and learn mainstream usage of terminology and drop your idiosyncratic redefinitions of the word “epigenetics” where in your definition “DNA Methylation and Histone Modifications” are peripheral, not central to epigenetics.

    I provided multiple citations, and at best you can come up with your twisted interpretation of Ptaschne, and idiosyncratic definition of transcription factors.

    Failing that – I will have no option but to invoke the neat “ignore” function.

    Go for it!

30. stcordova,

    Sal: That is one generation. One. Uno.

    I’m not so dim as to think an imprinted chromosome cannot get into a zygote.

31. Think about it. You have a gene that does better in males than females. You need to make sure that it is expressed in males and suppressed in females. How in hell are you going to do that while at the same time maintaining a multi-generational methylation state? Don’t men have daughters?

32. stcordova: I’m demonstrating your lack of understanding by cutting and pasting what you should already understand.

    Pasting a large block of text merely shows your ability at pasting large blocks of text – unless you are going to explain how said block of text demonstrates Tom’s lack of understanding of epigenetics or otherwise.

33. Sal, you bolded two sentences in support of your contention that a methylation pattern is inherited across more than one generation:

    in higher vertebrates, there is a “global” methylation pattern involving complete methylation of CpG sites genome-wide

    and

    the primary regulatory role of the DNA methylation system is highly conserved in higher vertebrates.

    Neither of these supports your contention, because neither indicates multi-generational inheritance of a given methylation state (as opposed to regenerating that state afresh). Ask your professors, if you doubt my veracity.

34. Alan,

    I’m demonstrating my understanding of these topics to my professors with each assignment.

    I’ve cut and pasted from mainstream literature and Tom Meuller has yet to defend his assertion that DNA methylation and histone modifications are peripheral to epigenetics. He’d be laughed out of my graduate school classes for saying nonsense like what he is saying.

    You want to believe Tom over me, that’s fine. But here is one of the NIH classes I’m taking. It is a pre-approved intra-institutional elective for a doctoral program in cell biology at my alma mater where I got an engineering degree.

    Search on Bioc 532 at this website of my alma mater:

    http://krieger.jhu.edu/cmdb/wp-content/uploads/sites/58/2016/01/CMDB-Approved-Electives-1.pdf

    http://cmdb.jhu.edu/courses/pre-approved-electives/

    The JHU website refers to this NIH class:
    https://faes.org/sites/default/files/files/FAES%20Catalog%202015-16%20FINAL.pdf

    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.

    Alan wrote:

    unless you are going to explain how said block of text demonstrates Tom’s lack of understanding of epigenetics or otherwise.

    Tom says DNA methylation and histone modifications are peripheral to epigenetics, I gave numerous citations otherwise. I refuted his points with literature.

    Additionally, I think Allan Miller is mistaken on epigenetic imprinting. I have to take exams on the topic, and I don’t think I’m going to agree with his insistence that epigenetic imprinting is not heritable! I’d get that answer wrong on the exams.

    No need to be so tribal and try to save face.

    Just because I’m a creationist doesn’t mean I can’t understand some of mainstream literature.

35. stcordova: I’m demonstrating your lack of understanding by cutting and pasting what you should already understand.I’m just driving home the point to readers of this thread how far out in left field your idiosyncratic non-standard usage of the term “epigenetics” is.

    GREAT!

    Then explain to me my own lack of understanding of exactly how epigenetics operates by providing your own explanation in your own words of what is happening with mules’ and hinnies’ imprinting… as I have repeatedly requested!

    I await with bated breath – your elucidation and my betterment!

    ITMT – I never said nucleosome modification was unimportant! I said it was a result and not a cause of epigenetic memory and therefore peripheral to the EPIGENETIC story.

    Fer crying out loud – the pretty pictures on the http://learn.genetics.utah.edu site indicate as much!!! You just don’t seem to understand your own cuts & pastes!!!

    Allow me to repeat myself – Nucleosome Modification is of course important, explaining my earlier references to the IMPORTANT roles of heterochromatin and facultative heterochromatin.

    How about another 24 hours before we all agree to finally drive the stake into this zombie-thread?!

36. Allan:

    neither indicates multi-generational inheritance of a given methylation state (as opposed to regenerating that state afresh).

    Good gravy, I just provided several citations of transgenrational inheritance of some methylation marks!

    We actually don’t know the complete mechanism of how they are inherited, but there is no question some of the methylation marks are inherited and additionally even the developmental changes in the methylation marks are inherited — that is to say, some of the differing methylation patterns between somatic cell types are inherited and we don’t know exactly the mechanism, but they keep showing up over and over between generations and between species.

    Ask your professors, if you doubt my veracity.

    Sorry Allan, I’m not going to ask such a dumb question that was gone over and over again in class. Some epigenetic marks are heritable some are not, the heritable ones are being studied especially by the 200 million dollar NIH Roadmap epiginomics project, and some of my professors are affiliated with the project to varying degrees:

    http://www.roadmapepigenomics.org/

    I’m mention my class because you guys keep saying I don’t understand. How does what you guys say line up with my good grades in the very classes that teach these issues? I’m trying to point out Tom is mistaken big time and you not as much, but you are still mistaken.

    Sorry to disagree, but some epigenetic marks have to be inherited for the health of the individual. The details of how that inheritance is mechanically carried out, no one really knows since as can be seen from the photo in the OP, the methylation marks are rebooted.

    They even refer to this as “epigenetic reprogramming”:

    http://hmg.oxfordjournals.org/content/14/suppl_1/R47.long

    During development of multicellular organisms, different cells and tissues acquire different programmes of gene expression. It is thought that this is substantially regulated by epigenetic modifications such as DNA methylation, histone tail modifications and non-histone proteins that bind to chromatin (1,2). Thus, each cell type in our body has its own epigenetic signature which reflects genotype, developmental history and environmental influences, and is ultimately reflected in the phenotype of the cell and organism. For most cell types in the body, these epigenetic marks become fixed once the cells differentiate or exit the cell cycle. However, in normal developmental or disease situations, some cells undergo major epigenetic ‘reprogramming’, involving the removal of epigenetic marks in the nucleus, followed by establishment of a different set of marks (3–5) (Fig. 1). In particular, this happens upon fertilization when many gametic marks are erased and replaced with embryonic marks important for early embryonic development and toti- or pluripotency. Major reprogramming also takes place in primordial germ cells (PGCs) in which parental imprints are erased and totipotency is restored.

    Both the mechanism and the function of paternal genome demethylation are unknown.

    The “reprogramming program” is heritable, but how it is implemented is unknown.

    The following relates to the OP by the way where I said epigenetic marks are RAM:

    http://www.nature.com/nature/journal/v414/n6859/full/414122a0.html

    Reprogramming of genome function through epigenetic inheritance

    These mechanisms involve heritable but potentially reversible modifications of DNA, primarily methylation of CpG (cytosine–guanine) dinucleotide1.

    See that, epigenetic INHERITANCE.

    Additionally:

    Although the mechanisms that perpetuate cell memory are naturally robust and reliable, they can be erased under some circumstances. The most pronounced manifestation of this erasure occurs when a differentiated somatic nucleus is transplanted back into an oocyte, which results in the restoration of totipotency4, 5, 6, 7.
    …

    There are potential mechanisms that can allow differentiated cells to perpetuate the ‘molecular memory’ of the developmental decisions that created it.

    ….
    as the inactive X chromosome can be reactivated in the somatic nucleus, although the molecular memory of the inactive X chromosome is retained,

    …

    And additionally to refute Allan Miller’s comment:

    Allan Miller:

    The obvious place to store epigenetic gender marking for both erasure and rewrite (and, indeed, X inactivation) is on the chromosome itself, or its chromatin. Storing it ‘in the cytoplasm’ seems like a clunky and error-prone way to do it.

    That disagrees with researchers in the field who argue for cytoplasm (as I argued since I got it from them):

    A less well explored but a highly significant consequence of genomic imprinting is that the oocyte cytoplasmic factors have apparently evolved and acquired complex properties in mammals that are required to enhance and maintain the epigenetic asymmetry between parental genomes in the zygote (refs 8, 10–13, and K. Arney et al. unpublished data). These factors could have important consequences for reprogramming of a somatic nucleus to totipotency when transplanted into the oocyte. One key objective in this field is to gain a detailed knowledge of the mechanisms involved in the erasure of existing epigenetic states and establishment of new modifications for totipotency and during imprinting. These studies will allow us to assess more precisely events associated with reprogramming of somatic nuclei to a pluripotent or a totipotent state. The analysis of epigenetic mechanisms involved is also crucial for our ability to manipulate pluripotent stem cells and for the derivation of a range of differentiated cell types from pluripotent embryonic stem cells.

37. stcordova,

    I’m demonstrating my understanding of these topics to my professors with each assignment.

    I dare say.

    You want to believe Tom over me, that’s fine.

    I’m a spectator in your dispute with Tom. My specific interest here is in the carriage of imprinted epigenetic marks across multiple generations (>1). Which I say does not happen, and you have provided no evidence to the contrary.

    Look at the cartoon you pasted. Parental marks are WIPED. Then they are REWRITTEN according to the gender of the individual producing the gametes. They aren’t COPIED, and they can’t be across multiple generations, because of the binary alternation between male and female descendants as you go down a lineage. It cannot be plainer. I don’t understand your refusal to see this:

    (To Alan) Additionally, I think Allan Miller is mistaken on epigenetic imprinting. I have to take exams on the topic, and I don’t think I’m going to agree with his insistence that epigenetic imprinting is not heritable! I’d get that answer wrong on the exams.

    Clearly, imprinting mechanisms are heritable. That is how you get stable gender-specific expression/repression. But that is not the same thing as saying that a particular methylation state is heritable across multiple generations – especially not imprinted states, which are BINARY and GENDER-SPECIFIC.

    It’s the difference between having your own inherited dog-eared copy of a book, and getting a new one. In both cases you end up with the same ‘text’. But you don’t (and can’t) keep the original book across multiple generations if gender is involved.

    When you generate sperm, your ‘books’ all have MALE written on the cover. Your wife’s all have FEMALE written on them. This info is used in the zygote to imprint. But that child (if female) does not pass on her mother’s copy of the imprint. She writes FEMALE on ALL her chromosomes, yours and your wife’s. Your sons meanwhile write MALE. Previous methylation states are ‘forgotten’.

    The corollary of your ‘tribalism’ taunt is your refusal to take anything an TSZ-er says as true. But it is clear to me that, for some reason, you are misunderstanding the role of gender in imprinting, when gender is what it is all about.

38. stcordova,

    Good gravy, I just provided several citations of transgenrational inheritance of some methylation marks!

    We were talking, all along, of those involved in gender-specific expression – imprinting. The maximum transgenerational inheritance is 1 (ie parent to child). Prove me wrong on that, not on something I have offered no opinion on.

39. stcordova,

    That disagrees with researchers in the field who argue for cytoplasm (as I argued since I got it from them):

    Until someone comes up with an actual mechanism, rather than you coming up with quotes that you think support your case, it still makes far more sense to mark the chromosome which is to be imprinted than anything else. What persuades you otherwise? Do you think it makes more sense to hold a chromosome’s identity anywhere other than on the chromosome itself? Would you keep your kids’ clothing labels in a drawer?

40. I don’t know where the proteins and RNAs in cytoplasm are supposed to come from, either, if not DNA.

41. Allan Miller: Until someone comes up with an actual mechanism, rather than you coming up with quotes that you think support your case, it still makes far more sense to mark the chromosome which is to be imprinted than anything else.

    Hi Allan

    I am wondering about the possibility that standard textbook orthodoxy (as quoted by Sal) may seem to be inadvertently implying that paternal and maternal chromosomes can still carry different epigenetic tags elsewhere other than single copy genes, even after “demethylation”, which is in fact represents only “partial erasure” as it were. That would rescue the bandwidth-jamming cut&paste version of events that Sal keeps heaping on our laps.

    The part of that I cannot seem to wrap my head around is the hinny vs mule conundrum. Clearly their differences cannot be at the level of “epigenetic marking” of paternal vs maternal chromosomes given both chromosome compliments are identical in both scenarios (presuming both the offspring hinny and the mule are females).

    Leaving me no other alternative but to question your suggestion that:

    Allan: The obvious place to store epigenetic gender marking for both erasure and rewrite (and, indeed, X inactivation) is on the chromosome itself, or its chromatin.

    I would think that perhaps some sort of invocation of miRNA would be a better explanation.

    I am curious how you would respond – but please, only after 24 hours such that Sal has an opportunity to redeem himself.

42. stcordova

    That disagrees with researchers in the field who argue for cytoplasm (as I argued since I got it from them):

    Sal – so far your bandwidth-jamming cut&paste version of events has failed the Turing Test.

    Notice that I have delivered to you a gift on a silver platter in my last response to Allan.

    I have spelled out in detail exactly how that question needs to be approached.

    You are welcome!

    I await your epigenetic explanation of how female hinnies differ from female mules with bated breath. Betterment is always welcome and I thank you in advance!

43. TomMueller,

    OK Tom, I’ll hang fire – except to say that it is still the ‘obvious’ place! Biology is not obliged to conform to my expectations, of course.

44. I, too, eagerly await Sal’s response to the hinny/mule question. I may have a follow-up question or two about the early, unsuccessful, sheep cloning experiments…

    So far, I agree 100% with Allan Miller.

45. DNA_Jock:..the early, unsuccessful, sheep cloning experiments…

    Sal might like to meet Dolly.

46. DNA_Jock:
    I, too, eagerly await Sal’s response to the hinny/mule question. I may have a follow-up question or two about the early, unsuccessful, sheep cloning experiments…

    So far, I agree 100% with Allan Miller.

    After rereading the thread – I think I now understand where Allan is coming from.

    ITMT – Me too… I am eager to hear Sal in his own words.

    Let’s give Sal another hint…
    Sal – your answer must include three words: Hinny, Mule & some version of the word “erase”.

    Here is another hint: Your task will be made easier if you actually refer your own recent post and to the very diagram you yourself posted – at 12:12 pm when you commented that “a picture is worth a thousand words”.

    Looking forward to hearing from you.

47. Alan Fox: Sal might like to meet Dolly.

    I had the pleasure of hearing Ian Wilmut talk about why the early attempts failed (yes: imprinting); he’s a funny guy…

48. Those identical twins don’t look identical to me.

49. Allan:

    Look at the cartoon you pasted. Parental marks are WIPED. Then they are REWRITTEN according to the gender of the individual producing the gametes. They aren’t COPIED, and they can’t be across multiple generations, because of the binary alternation between male and female descendants as you go down a lineage. It cannot be plainer. I don’t understand your refusal to see this:

    Thank you for you comment as it highlights why we are talkiing past each other on the topic of imprinting.

    If I have a black board, call it a “Parent” and it has markings on it and then I have another blackboard, call it “Child”, and I put the same markings on the child, then erase them and wipe them clean and put the same markings on it, does it not mean that there is not transgenerational inheritance of those markings? Absolutely not. In the process of me doing this, I served as the temporary store of the markings as I copied them from parent to child, even if I decided to do a wiping process. This actually seems reasonable like a reboot and reloading of the RAM in the process of epigenetic reprogramming, and yes, “reprogramming” is the terminology used!

    The fact that several of the marks must appear in the same locations on the same imprinted genes throughout several generations is effectively a copy of the epigenetic marks. The epigenetic marks are transgenerationally inherited.

    Not all epigenetic marks are transgenerationally inherited, but some obviously are, some can acquired marks can be transgenerationally inherited, but some are obviously very persistent and we don’t know the mechanisms of the highly persistent marks.

    If you assert imprinted marks, especially those important to development, aren’t inherited, then how do you account for them appearing generation after generation and even being “evolutionarily conserved” (to you evolutionary phraseology). I appreaciate the conversation, but I think you’re straining a gnats an letting camls through.

    That’s why I’m rather sure it’s a dumb question to ask a professor, “are epigenetic marks on imprinted genes inherited?” Well gee, the grand parents have those marks, and so do the kids, was that a coincidence?

50. I don’t know where the proteins and RNAs in cytoplasm are supposed to come from, either, if not DNA.

    Such reasoning is wrong, DNA is necessary but not sufficient to code a protein.

    Btw, enucleated zygotes have been known to replicate without DNA since they seem front loaded with sufficient mRNA to keep replicating to the blastula phase.

    Put DNA in isolation, it won’t make proteins! Therefore DNA doesn’t contain all the information to make proteins, one needs functional RNAs and proteins in the right state.

    Stuff human DNA into a plant cell, it won’t become a human. DNA isn’t the total information and technology source.