May 26, 2020 | David F. Coppedge

Epigenetics Complicates Evolutionary Theory

Evidence has been mounting that other mechanisms and codes that regulate the genetic code are just as vital as DNA itself.

This is a great introduction into the significance of epigenetics.

Cellular life gets more complicated the closer molecular biologists look. Darwinians had their work cut out for them trying to explain the origin of the genetic code. How will they fare with epi-genetic (“above” the gene) codes that regulate DNA? How would any “primitive” cell ever survive without these additional controls that make sure the right genes are turned on and off? In addition, it is becoming clear that epigenetics has much to do with adaptation to new environments.

Here are some recent news articles about the burgeoning field of epigenetics.

The Clothesline and Pigeon Analogy

Under-researched mechanism in fast-moving field of epigenetics focus of new study (University of New South Wales, Australia). The old picture of DNA as the master, directing the synthesis of proteins, is being replaced by a new picturesque analogy:

“Think of DNA as a clothesline, epigenetic chemical marks as pegs, and regulatory proteins – that bind to specific DNA sequences and control which genes turn on or off – as pigeons that want to sit on the clothesline,” Prof Crossley says.

“If the line is covered with pegs, pigeons won’t be able to land. We used mice to look at a key gene in blood and changed it so it either had or did not have a peg, and found this determined whether a gene regulatory protein could bind and turn off the gene. The gene stayed on until the peg was removed.

What are these pegs? They are chemical tags made of methyl groups, acetyl groups and others that attach to DNA. In addition, the pegs attach to histone proteins within chromatin, the balls of material around which DNA wraps to create its higher-order structure (i.e., above the double helix). Enzymes place these pegs on the ‘clothesline’ to determine what genes become accessible to the transcription machinery or not.

“In a nutshell, our study demonstrates that methylation – the biological process that adds methyl groups like epigenetic chemical marks to DNA – can affect the binding and activity of that protein in gene expression. It had long been suspected this would be the case but having a solid foundation, with one mark and one DNA-binding protein gives you the components with which to build.”

We begin to see that DNA is covered with portable switches that a process places on genes to regulate them. This sheds light on how different types of cells in the body express different genes. It also illuminates how environmental signals can alter the expression of genes. Scientists are finding that some of those altered epigenetic markers are heritable, and can affect future generations. But what controls the arrangement of these epigenetic switches? This article doesn’t say. It must be some kind of upstream code that is responsive to outside signals. Scientists have been considering a “histone code” for years, but little has been written about what process decides what coded messages (e.g., methyl groups) are to be placed onto the histones or nucleotides.

For those interested in the details, the paper behind the press release is open-access. published in Nature Communications, 22 May 2020, by Lu Yang et al., “Methylation of a CGATA element inhibits binding and regulation by GATA-1.” The authors make it clear that “the mechanisms by which the DNA methylation influences gene expression and differentiation are still not fully understood.”

The paper says nothing about evolution, by the way.

Epigenetics Determines How Blood Cells Differentiate

Red blood cells and other blood components circulate through arteries, capillaries, and veins.

At the crossroads: Scientists investigate epigenetic mechanisms of blood cell differentiation (Max Planck Institute of Immunology and Epigenetics). The same stem cells in bone marrow differentiate into red blood cells (RBCs, also called erythrocytes), white blood cells, and platelets. How does that happen? Before looking into the role of epigenetics in the process, they give some “wow” facts about the production rate of blood cells in the body.

On average, the human body contains 35 trillion red blood cells (RBCs). Approximately three million of these small disc-shaped cells die in one second. But in this second, the same number is also produced to maintain the level of active RBCs. Interestingly, all of these cells undergo a multi-level differentiation process called erythropoiesis. They start from hematopoietic stem cells (HSCs), the precursors to every blood cell including all types of immune cells, and differentiate then, firstly, into multipotent progenitor cells (MPPs) followed by a gradual process of specialization into mature red blood cells.

These facts are not merely of academic interest. Your health depends on them.

If this differentiation process fails, it can be detrimental to our health. For instance, if fewer HSCs choose to follow the RBCs roadmap, the individual will be prone to develop anemia. Abnormalities in the immune cell roadmap, on the other hand, have been associated with the onset of leukemia.

Researchers at the Max Planck Institute looked at the role of an enzyme named MOF in keeping blood cell differentiation working properly. It’s an epigenetic regulator that helps “orchestrate” the fate of HSCs. What we learned above about histones and chromatin now comes into focus in this story:

“One of the most important intrinsic cues governing cell developmental processes is the modulation of the chromatin landscape,” says Asifa Akhtar. In our cells, DNA is packaged around histone proteins to make the chromatin structure. This packaging plays a crucial role in cell type-specific gene regulation and, of course, also in erythroid differentiation. In its default state chromatin is not “permissive”, meaning genes are switched off. But shifting histones opens the chromatin and promotes gene expression.

That’s where MOF comes in. It knows exactly where to tag a particular histone (H4) at a particular site (K16ac), in order to “switch on” the hitherto non-permissive state of precursor genes for blood cell differentiation.

But now the question arises, what signals MOF to get busy? Scientists know that the upstream processes “fine-tune” the production of differentiated blood cells. They also know that when the tuning is off, the ‘orchestra’ can’t play, and diseases result. But how does the body know when to send the agent that flips the switch? Stay tuned. the burgeoning science of epigenetics is bound to get more and more interesting.

DNA coils and supercoils in a highly regulated way to pack the genome into chromosomes. Epigenetic tags placed on nucleotides and on histones form a higher-order code that affects transcription of the genetic code.

Discovery of genes required for body axis and limb formation by global identification of retinoic acid–regulated epigenetic marks (PLoS Biology). For a final example, we won’t go into detail, but this paper illustrates some of the complexity of understanding epigenetics. The authors try to figure out which epigenetic factors control body axis and limb formation in mouse embryos. It’s complicated. No wonder the authors only speculate about evolution once, and (as usual), tell a just-so story, ending with an appeal to futureware:

Thus, it appears that the ancestral function of Nr2f genes in fish was to control heart formation but that during evolution, another function to control body axis formation was added. Future studies can be directed at understanding the mechanism through which Nr2f1 and Nr2f2 control body axis formation.

Another function “was added”? How, exactly, did that happen? They don’t say. Their only other mention of evolution concerns an attempt to look for “conserved” (un-evolved) epigenetic markers.

It appears best to ignore evolution—you know, that concept where ‘nothing in biology makes sense except in the light of evolution’—when researching epigenetics.

Dr Woodward illustrates use of tRNA and DNA.

Recommended Resource: A picture is worth a thousand words. How does DNA work? How do transcription and translation work? How does methylation (a part of epigenetics) work? Dr Tom Woodward has created working models of these that you can see explained at Short videos explain the parts in the kits that are available for purchase. Recently added were “DNA and Friends” including models of transfer RNA (tRNA) and amino acids. These are great resources for teachers or home-schooling parents to introduce students to the chemical-coded workings of genetics and epigenetics.

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