An epigenetic trap (the sequel)

By: James V. Kohl | Published on: January 24, 2015

(click to enlarge)

I will post this “sequel” before the “prequel” about light-induced amino acid substitutions because more attempts are being made to deny that the fact my colleagues and I detailed how epigenetic traps links the morphology and behavior of species from microbes to man. Support for the link from one epigenetic trap to cell type differentiation was included in the molecular epigenetics section of our 1996 review, which detailed how RNA-mediated chromatin remodeling occurs.
From Fertilization to Adult Sexual Behavior:
Excerpt: “…another kind of epigenetic imprinting occurs in species as diverse as yeast, Drosophila, mice, and humans and is based upon small DNA-binding proteins called “chromo domain” proteins, e.g., polycomb. These proteins affect chromatin structure, often in telomeric regions, and thereby affect transcription and silencing of various genes (Saunders, Chue, Goebl, Craig, Clark, Powers, Eissenberg, Elgin, Rothfield, and Earnshaw, 1993; Singh, Miller, Pearce, Kothary, Burton, Paro, James, and Gaunt, 1991; Trofatter, Long, Murrell, Stotler, Gusella, and Buckler, 1995). Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism…”
Others continue to ignore the conserved molecular mechanisms we detailed. See also: Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. March 15, 2012
Conclusion: “Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans (Keller et al., 2007; Kohl, 2007; Villarreal, 2009; Vosshall, Wong, & Axel, 2000).”
A classic example of someone who ignored the mechanisms is linked below:
How keeping active pays off in the olfactory system December 13, 2012 (see also the comments section)
Excerpt: “…this model provides an elegant balance between plasticity and adaptation; although the potential to detect a wide range of odours, afforded by the exceptional number of genes for receptors, remains intact, the sensory organ becomes ‘tuned’ and sensitized to odorants relevant to its habitat.”
I asked: “Is what’s being elucidated the bottom-up epigenetic effects on stochastic gene expression via chromatin remodeling, which is controlled by the top-down epigenetic effects of pheromones on reproduction in species from microbes to man? Kohl, J.V. (2012) Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors. Socioaffective Neuroscience & Psychology, 2: 17338. DOI: 10.3402/snp.v2i0.17338.”
Stavros Lomvardas replied: “The article elucidates how the environment can broadly influence gene expression through an epigenetic effect chromatin – the way DNA is package and organized. This allows the environment to influence sensory function, to tune the olfactory sense to better suit the surrounding environment, because these environmentally regulated chromatin changes are coupled to cell longevity. This results in a change in the distribution of cells in the tissue that have made particular stochastic choices, where the stochastic choice is which olfactory receptor to express, without affecting the mechanism of stochastic gene expression.”
My comment: In the review he co-authored, Lomvardas integrated part of what we detailed about chromatin remodeling in our 1996 Hormones and Review. Then he answered my question by rewording what I asked. He might just as well have claimed that “Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans.” That would have made it perfectly clear that he was simply parroting the findings from two decades of my works, including works with others.
When other researchers display such despicable behavior, it is typically repeated, which is what Lomvardas did. See for another example, which followed after my publication of: Nutrient-dependent/pheromone-controlled adaptive evolution: a model June 14, 2013
My conclusion: “Minimally, this model can be compared to any other factual representations of epigenesis and epistasis for determination of the best scientific ‘fit’.”
My comment: Next, our 1996 representation of an an RNA-mediated pheromone-controlled epigenetic trap, and everything else I had detailed since then, showed up in:An Epigenetic Trap Stabilizes Singular Olfactory Receptor Expression July 18, 2013
Excerpt: “Our data, together with the established requirement of intact OR protein for the generation of the feedback signal, lead to the following regulatory model: LSD1, in complex with an as yet-
unidentified H3K9me3 demethylase, desilence a previously heterochromatinized OR allele, allowing H3K4 trimethylation and transcriptional activation. If this allele encodes an intact OR, then it will induce Adcy3 expression, LSD1 downregulation, and OSN maturation, generating an ‘‘epigenetic’’ trap that will preserve OR expression, cellular identity, and targeting specificity, as long as the underlying transcription factor milieu remains unaltered (Figure 7A).
My comment: Understanding the molecular epigenetics of nutrient-dependent RNA-directed DNA methylation that enable the pheromone-controlled epigentic trap could have prevented the confusing representation that began in 1996 and culminated in 2015 with a horrid misrepresentation of biologically-based cause and effect.
It will be interesting to see if Lomvardas ever publishes anything that does not parrot two decades of my published works. However, he is not the only parrot.
In August 1996, two UCSF researchers discussed cell type differentiation in S. cerevisiae. See: A Deubiquitinating Enzyme Interacts with SIR4 and Regulates Silencing in S. cerevisiae (1996)
Excerpt: “As silencing in both yeast and Drosophila is similarly enhanced by mutations in particular ubiquitin processing enzymes, the regulation of silencing by these enzymes appears to be an evolutionarily conserved process.”
My comment: I reiterate, in December 1996, two independent researchers and first author Milton Diamond detailed how RNA-mediated cell type differentiation occurs in species from S. cerevisiae to mammals. See: From Fertilization to Adult Sexual Behavior
Excerpt 1) “Small intranuclear proteins also participate in generating alternative splicing techniques of pre-mRNA and, by this mechanism, contribute to sexual differentiation in at least two species, Drosophila melanogaster and Caenorhabditis elegans (Adler and Hajduk, 1994; de Bono, Zarkower, and Hodgkin, 1995; Ge, Zuo, and Manley, 1991; Green, 1991; Parkhurst and Meneely, 1994; Wilkins, 1995; Wolfner, 1988). That similar proteins perform functions in humans suggests the possibility that some human sex differences may arise from alternative splicings of otherwise identical genes.”
Excerpt 2) “Parenthetically it is interesting to note even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995).”
My comment: During the past two decades, ideas about mutations and the silencing of genes by enzymes have changed. Serious scientists have learned that RNA-directed DNA methylation leads from RNA-mediated amino acid substitutions to the de novo creation of olfactory receptor genes and the epigenetic trap that enables cell type differentiation in all cells of all individuals of all species via conserved molecular mechanisms. See: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
One of the co-authors of the 1996 UCSF publiication on gene silencing is now at Harvard. The molecular epigenetics from our 1996 review are reported as if they are “epigenetic phenomena”. He co-authored: RNA-mediated epigenetic regulation of gene expression (2015).
Epigenetic phenomena are “Phenomena in which changes in gene expression occur without a corresponding change in the DNA sequence; such changes are stable in the absence of initiating signals.”
Our representation of RNA-mediated cell type differentiation has become “paramutation.”
Again see: RNA-mediated epigenetic regulation of gene expression (2015). Paramutation is “The ability of a silent allele to convert an active allele to the silent (and paramutagenic) form. It was first described in Zea mays.”
Sarcasm alert! Zea mays has not become a new species via epigenetic phenomena that led to any paramutation. It is still known as corn.
The RNA-mediated events that led to cell type differentiation in plants and animals link the epigenetic landscape to the the physical landscape of DNA in the organized genomes of species from microbes to man. The question arises: Does the same epigenetic path and RNA-mediated events link nutrient-dependent pheromone-controlled cell type differentiation from “epigenetic phenomena” and “paramutations” to small intranuclear proteins; alternative splicing techniques of pre-mRNA; and sexual differentiation of cell types?
If so, our 1996 review; my 2013 review; and the 2015 review co-authored by Danesh Moazed provide details about conserved molecular mechanisms that link cell type differentiation in species from microbes to man. The obvious answer to all questions about cell type differentiation is this: One path links the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man. We detailed every aspect of what was known about RNA-mediated path in 1996.
Along that path is an epigenetic trap. Many researchers now try to ignore the trap, pretend it is not there, or claim that they knew everything that anyone needed to know about it. Metaphorically, many researchers may not have looked back to their works in the 1990’s to see if the epigenetic trap was following them. Instead, some of them inferred that the molecular mechanisms of species diversity in plants were different than the molecular mechanisms of species diversity in animals. How could the molecular mechanisms that enable biodiversity be different in plants and animals? In “An Epigenetic Trap (the prequel)” I will detail the fact the physics, chemistry, and molecular biology must link the epigenetic landscape to the physical landscape of DNA in the organized genomes of all plants and all animals via conserved molecular mechanisms.
Until then, you can expect to read more about things like epigenetic phenomena and paramutations because evolutionary inferences are still quite common. However, those who struggle to make sense of the inferences now struggle to make others think they have not been trapped by what has been learned about molecular epigenetics.
In 1996, we linked what was known about the epigenetic landscape to the physiology of reproduction via the metabolism of nutrients to species-specific pheromones. Some researchers now know that pheromones enable the species-specific fixation of RNA-mediated amino acid substitutions, although they may not know they know it.
James Shapiro explains cell type differentiation starting with species-specific pheromones in yeast on page 20 of his 2011 book. See the chapter citations here: Evolution: A View from the 21st Century
We started with pheromones in yeasts in our 1996 Hormones and Behavior review:
Excerpt 1) “…chemosensory communication is ubiquitous throughout life among species from single celled yeasts to primates, including humans (see for review Kohl and Francoeur, 1995). Chemical stimuli, odors, including pheromones, are essential components of reproductive sexual behavior in most, if not all, species. Pheromonal communication has been seen to elicit physiological and behavioral changes that benefit both male and female individuals and, in humans, these olfactory sensations seem to exert their influence whether or not an individual is conscious of odor detection.”
Excerpt 2) Parenthetically it is interesting to note even the yeast Saccharomyces cerevisiae has a gene-based equivalent of sexual orientation (i.e., a-factor and alpha-factor physiologies). These differences arise from different epigenetic modifications of an otherwise identical MAT locus (Runge and Zakian, 1996; Wu and Haber, 1995).
In my 2012 review: Human pheromones and food odors: epigenetic influences on the socioaffective nature of evolved behaviors, I arrived at the same conclusion as every serious scientist, including Danesh Moazed, has arrived at since 1996. “Olfaction and odor receptors provide a clear evolutionary trail that can be followed from unicellular organisms to insects to humans (Keller et al., 2007; Kohl, 2007; Villarreal, 2009; Vosshall, Wong, & Axel, 2000).”
That is the only conclusion supported by experimental evidence of how the biophysically constrained chemistry of protein folding that links the molecular epigenetics of cell type differentiation via nutrient-dependent amino acid substitutions in species from microbes to man. However, Holoch and Moazed (2015) conclude: “Finally, the mechanisms by which lncRNAs participate in the recruitment of Polycomb proteins and other chromatin-modifying activities, particularly the molecular basis of specificity, remain poorly defined. We can look forward to answers to these questions and, if the recent past is a guide, to more exciting and unexpected discoveries about the roles of RNA in gene regulation.”
My comment: How could the molecular basis of chromatin-modifying activities in the context of species specificity be clearer? The molecular mechanisms of RNA-mediated epigenetic regulation of gene expression are nutrient-dependent and pheromone.controlled. It’s been 18 years since we detailed that fact in our Hormones and Behavior review. How could anyone not know it? Or, are others, like Lomvardas, simply pretending not to know what we detailed?
In Epigenetic inheritance uncoupled from sequence-specific recruitment (2014), senior author Moazed claims that “An attractive possibility is that as epigenetic states become established during transition from pluripotency to the differentiated state, reduction in the expression of H3K9 demethylases helps stabilize the differentiated state (52). In another example, down-regulation of the amine oxidase family histone demethylase LSD1 during activation of individual olfactory receptor (OR) genes in the mammalian nose has been suggested to create an “epigenetic trap” that prevents the activation of additional OR genes (53). More generally, H3K9 demethylases may act as surveillance enzymes that prevent the formation of spurious H3K9 methylated domains, which may lead to epigenetic mutations and gene inactivation.”
Moazed just linked nutrient-dependent pheromone-controlled cell type differentiation via RNA-directed DNA methylation and RNA-mediated amino acid substitutions to “…epigenetic mutations and gene inactivation.” What is the difference between epigenetic phenomena that lead to paramutations and epigenetic effects that lead to epigenetic mutations. The question arises: What is an epigenetic mutation? I claim the definition of the term “mutation” is a trap. It’s an epigenetic trap that was set for pseudoscientists who decided to claim that Darwin’s theory included mutations that led to the evolution of biodiversity.
Just as de Vries definition of “mutation” trapped evolutionary theories into touting their assumptions about how mutations led to evolution, the epigenetic trap leaves them stuck with their definitions and assumptions. Now we need definitions of epigenetic phenomena and paramutations. Why? Because the effects of olfactory/pheromonal input that link the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man are called “epigenetic mutations”.
Indeed, all the mutations that evolutionary theorists claimed somehow led to the evolution of biodiversity, can now be referred to as epigenetic mutations. If so, the claims still made by evolutionary theorists about Mutation-Diven Evolution may still sound convincing to the biologically uninformed.

Are you tired of being one of the biologically uninformed?

The epigenetic landscape is linked to the physical landscape of DNA in organized genomes of species from microbes to man by nutrient-dependent pheromone-controlled amino acid substitutions that differentiate all cell types in all individuals of all species. Mutations perturb protein folding, they prevent the membrane potential changes are found to determine anterior-posterior axis in development and regeneration, as well as cell proliferation, differentiation and cancer (see [18] Membrane Potential Rules, SiS 52). That means mutated Genes Don’t Generate Body Patterns. Instead the explanation for the diversity of morphological and behavioral phenotype is Extensive Gains and Losses of Olfactory Receptor Genes in Mammalian Evolution
Excerpt 1) “It appears that the number of OR genes is determined primarily by the functional requirement for each species, but once the number reaches the required level, it fluctuates by random duplication and deletion of genes. This fluctuation seems to have been aided by the stochastic nature of OR gene expression.
Except 2 with my emphasis) “Why then did the number of OR genes change so dramatically in mammals but not in Drosophila? One possible explanation is the difference in the mechanism of gene expression system between mammals and Drosophila. In Drosophila, a specific OR gene tends to be expressed deterministically in a given olfactory neuron [32], [33]. Therefore, if an OR gene is duplicated or lost from the genome, the gene expression system may be disturbed. In mammals, however, one of the clustered OR genes in the genome is stochastically chosen to be expressed in each olfactory neuron [34]. Therefore, the expression pattern of OR genes appears to be considerably different among different individuals, and consequently the number of OR genes may change relatively easily in the evolutionary process [31]. Of course, this is a hypothesis at present, and it should be tested by experiments.”
Niimura, Yoshihito and Masatoshi Nei (2007) have been caught in an epigenetic trap. Their can be no differences in the mechanism of gene expression system between mammals and Drosophila, or between plants and animals. The biophysically constrained chemistry of protein folding must link the epigenetic landscape to the physical landscape of DNA in all living organisms via conserved molecular mechanisms of nutrient-dependent RNA-directed DNA methylation and the RNA-mediated amino acid substitutions that differentiate all cell types in all individuals of all species. Only pseudoscientists claim “…we will not consider geographical and ecological factors because of space limitation.” Serious scientists do not exclude any factors from their attempts to explain biologically-based cause and effect. Similarly, serious scientists do not claim that “(1) Mutation is the source of all genetic variation on which any form of evolution is dependent. Mutation is the change of genomic structure and includes nucleotide substitution, insertion/deletion, segmental gene duplication, genomic duplication, changes in gene regulatory systems, transposition of genes, horizontal gene transfer, etc. (2) Natural selection is for saving advantageous mutations and eliminating harmful mutations. Selective advantage of the mutation is determined by the type of DNA change, and therefore natural selection is an evolutionary process initiated by mutation. It does not have any creative power in contrast to the statements made by some authors.” (p. 196)
Those are the claims of pseudoscientists who cannot understand the fact that Life is physics and chemistry and communication.
That fact is what I will detail in “An epigenetic trap (the sequel)”