DNA Methylation and organized genomes

This open access review that is linked from the title (below) will appear in the next issue of Int J Biol Sci 2015; 11(5):604-617. doi:10.7150/ijbs.11218

It is a excellent, albeit incomplete, review of how nutrient-dependent RNA-directed DNA methylation and RNA-mediated amino acid substitutions link the epigenetic landscape to the physical landscape of DNA via the biophysically constrained chemistry of cell type differentiation and the physiology of reproduction in all genera.

The review is incomplete because they do not start with RNA-directed DNA methylation. They start with DNA methylation. They probably know that most serious scientists do not believe in theories that automagically link the epigenetic landscape to RNA-mediated protein biosynthesis and degradation, which is required to link the organized genomes of all genera.

For comparison, researchers who tout theories that do not link what is currently known about physics, chemistry, and molecular biology to cell type differentiation have not been considered to be serious scientists since Dobzhansky (1964) wrote: “…the only worthwhile biology is molecular biology. All else is “bird watching” or “butterfly collecting.” Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists! the only worthwhile biology is molecular biology. All else is “bird watching” or “butterfly collecting.” Bird watching and butterfly collecting are occupations manifestly unworthy of serious scientists!”

For an update on what serious scientists have learned about the molecular biology of nutrient-dependent cell type differentiation, see:

DNA Methylation, Its Mediators and Genome Integrity

Concluding sentences:  “Functional characterisation of the associated proteins continues to be an area of high interest, and accumulating in vivo data contribute an increasingly precise understanding of DNA methylation modes. These insights linking the genetic instability and epigenetic perturbations such as aberrant DNA methylation machinery may ultimately form the basis for novel therapeutic strategies and targets for the treatment of inherited, acquired and malignant diseases.”
For comparison, see: Mutation-Driven Evolution
Concluding sentences: “In other words, genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world. In this view of evolution there is no need of considering teleological elements” (p. 199).
See also: Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems
In my invited review of nutritional epigenetics, I wrote:
“Nutrient-dependent epigenetic effects on histone modifications and DNA methylation play an important role in stabilizing cell type identity and in orchestrating many developmental processes. For example, vitamin C appears to stimulate histone demethylases, which appear to alter the de novo creation of functional olfactory receptor genes (Adipietro, Mainland, & Matsunami, 2012; Blaschke et al., 2013; Jazin & Cahill, 2010; Lyons et al., 2013; Tan, Zong, & Xie, 2013).
Researchers recently rediscovered a nutrient-dependent epigenetic variant that links vitamin C to what is probably a glucose and glucose dehydrogenase-dependent base pair change. The base pair change results in addition of a methyl group to a cytosine base, which takes on a hydroxyl group to form different 5-hydroxymethylcytosines (5hmCs). Different 5hmCs are associated with differences in cell types that have the same genetic backgrounds. Nutrient-dependent epigenetically-marked bases help to explain how hundreds of cell types in the human body and in the brain (Kriaucionis & Heintz, 2009) are differentiated and how they maintain their glucose-dependent and other nutrient-dependent receptor-mediated identities (Wu et al., 2014).
For example, calcitriol is the active form of vitamin D. Its effects on the microRNA(miRNA)/messenger RNA (mRNA) balance appear to protect against perturbed protein folding, which is associated with colorectal cancer. MiRNA-627 targets the mRNA that encodes an enzyme linked to histone demethylation and amino acid substitutions that increase stability of hydrogen bonds in DNA, which are important to protein folding (Padi, Zhang, Rustum, Morrison, & Guo, 2013). Rarely does a week go by without yet another report that details cause and effect in the context of miRNAs (Follert, Cremer, & Beclin, 2014).”
In the abstract from DNA Methylation, Its Mediators and Genome Integrity, we read:
“DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.”
The difference in the two reviews is clear. In DNA Methylation, Its Mediators and Genome Integrity, they fail to link olfaction and nutrient-dependent pheromone-controlled feedback loops. The feedback loops are linked to chromatin loops and cell type differentiation via conserved molecular mechanisms of biophysically constrained hydrogen bonding and RNA-directed DNA methylation and RNA-mediated amino acid substitutions in species from microbes to man.
The substitutions link the epigenetic landscape to the physical landscape of DNA. For instance, nutrient-dependent pheromone-controlled feedback loops link chromatin loops to cell type differences in all cells of all tissues of all organs and all organ systems of vertebrates and invertebrates. I provided across-species examples of biologically-based cause and effect in my 2013 review: Nutrient-dependent/pheromone-controlled adaptive evolution: a model.  I concluded: “Minimally, this model can be compared to any other factual representations of epigenesis and epistasis for determination of the best scientific ‘fit’.”
The similarities in my model, my review of nutritional epigenetics, and DNA Methylation, Its Mediators and Genome Integrity include that fact that defects in DNA methylation contribute to genome instability and physiopatholgy including cancer.
Publication of my model led to the request for submission of my review of nutritional epigenetics, which was not published. Supposedly, no one could be found who would review it. This problem remains: If others do not link nutrient uptake to RNA-directed DNA methlyation, they leave out the basis for RNA-mediated cell type differentiation via amino acid substitutions.  For instance, see this excerpt from my 2012 review:

Among different bacterial species existing in similar environments, DNA uptake (Palchevskiy & Finkel, 2009) appears to have epigenetically ‘fed’ interspecies methylation and speciation via conjugation (Fall et al., 2007; Finkel & Kolter, 2001; Friso & Choi, 2002). This indicates that reproduction began with an active nutrient uptake mechanism in heterospecifics and that the mechanism evolved to become symbiogenesis in the conspecifics of asexual organisms (Margulis, 1998). In yeasts, epigenetic changes driven by nutrition might then have led to the creation of novel cell types, which are required at evolutionary advent of sexual reproduction (Jin et al., 2011). These epigenetic changes probably occur across the evolutionary continuum that includes both nutrition-dependent reproduction in unicellular organisms and sexual reproduction in mammals.

See also, my 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).

I cannot stress this fact enough: Without the link from olfactory/pheromonal input to RNA-directed DNA methylation and RNA-mediated cell type differentiation via amino acid substitutions, others are missing the critical link from ecological variation to ecological adaptations. What others are missing has led theorists to offer their ridiculous ideas about mutations and evolution for comparison to well-detailed facts about biologically-based cause and effect. Biologically-based cause and effect links species from microbes to man via what is currently known about physics, chemistry, and the conserved molecular mechanisms of epigenetic top-down causation.
The authors of DNA Methylation, Its Mediators and Genome Integrity can be credited for linking DNA methylation and cell type differentiation from
1) “…the involvement of few amino acids upstream of the MBD domain of MeCP2…
2) … the zinc finger domain of KAISO proteins… and a binding preference for two 5meCpG motifs in close proximity to a distinct base-flipping mechanism… that
3) … recognises and binds hemi-methylated DNA and acts in conjunction with DNMT1 to maintain DNA methylation… [and to] 4) …the presence of a weak but specific affinity for hemi- and fully-hydroxymethylated DNA…”
They cannot be credited for eliminating ridiculous theories about mutations and evolution from any further consideration whatsoever. By presenting the facts about DNA methylation and cell type differentiation without linking them to nutrient-dependent RNA-mediated amino acid substitutions, they may unknowingly be leading theorists to continue believing in pseudoscientific nonsense about mutations and evolution. Arguably, some serious scientists may not think they need to refute the pseudoscientific nonsense of evolutionary theories. Others are doing it. See: Combating Evolution to Fight Disease. However, the efforts of serious scientists fall short of the efforts by evolutionary theorists to keep others who are biologically uniformed from examining what is currently known. See also: Beyond Genetic Evolution. A Conversation With Eva Jablonka
Excerpt: “This is a good opportunity to move to the second dimension of evolution, epigenetics. Now we do have mechanisms, and we can begin to understand how epigenetics counts as an inheritance system.”
My comment: Epigenetics is NOT the second dimension of evolution. Epigenetics links RNA-directed DNA methylation to RNA-mediated cell type differentiation via amino acid substitutions. The amino acid substitutions link nutrient-dependent morphological and behavioral phenotypes to biodiversity via the physiology of their reproduction, which is controlled by the metabolism of nutrients to species-specific pheromones in species from microbes to man.  See: The Man Who Bottled Evolution. Ask an evolutionary theorist when epigenetics became the second dimension of evolution in any context of what has been attributed to mutations despite Dobazhansky’s claim that: “…the so-called alpha chains of hemoglobin have identical sequences of amino acids in man and the chimpanzee, but they differ in a single amino acid (out of 141) in the gorilla” (p. 127). See: Nothing in Biology Makes Any Sense Except in the Light of Evolution
See also: Evolutionary resurrection of flagellar motility via rewiring of the nitrogen regulation system.
What is obviously an example of nutrient-dependent pheromone-controlled ecological adaptation was reported in the context of re-evolution of the bacterial flagellum, which “re-evolved” over- the-weekend.
Excerpt: “We identified a tractable model for gene network evolution and observed, in real time, the rewiring of gene networks to enable the incorporation of a modified component (NtrC′) creating a novel regulatory function by a highly repeatable two-step evolutionary pathway with the same point mutations often recurring in independent lineages.”
My comment: If others are going to begin claiming that epigenetics is the second dimension of evolution, they will need to explain how re-evolution of a complex structure occurred in 96 hours as if by the magic of mutations to fit Masatoshi Nei’s conclusion that: “…genomic conservation and constraint-breaking mutation is the ultimate source of all biological innovations and the enormous amount of biodiversity in this world” (p. 199)
For comparison to that ridiculous claim, see Force for ancient and recent life: viral and stem-loop RNA consortia promote life:
Excerpt: “… the massive creative power of a cooperative RNA consortium (QS-C) remains crucial for life. QS-C was made known to us only recently by virus evolution (e.g., HIV-1). Its role in the origin of life, the emergence of complexity and the creation of group identity should now receive our combined attention” (p. 8).
To be continued: See DNA Methylation and organized genomes (2)

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