Epigenetics drives genetics; & why it matters

Photo credit: Jakob Rosen via Unsplash.

The power of epigenetic processes on genes continues to be an important topic in biology. Epigenetic processes control which genes are translated and which are silenced, what concentrations of transcripts are needed, and how molecular machines assemble at the right times and in the right places to direct gene products to their operational destinations. If the score is an argument for the design, how much more the organization that brings it to life in the halftime show of a marching band?

The guardian of the epigenome

The p53 protein has long been referred to as the “guardian of the genome” for its key role in tumor suppression. Today, some German researchers call it “the guardian of the (epi)genome”. News from the University of Konstanz tells how a research team led by Ivano Amelio has thoroughly examined how p53 works.

Cells – and their DNA integrity – are particularly at risk when they divide, as they duplicate their DNA in the process. “As in any other replication process, such as photocopying a document or copying a digital file, it is disastrous if the model moves or changes during copying. For this reason, genes cannot be transcribed – that is, used as templates for proteins – while DNA is being copied,” says Amelio. If they are transcribed anyway, serious disruptions occur, which can lead to cancer-promoting mutations. Findings by Amelio and his team, which now appear on the cover of Cell Reports, show that knocking out p53 promotes such copy damage. They found that p53 normally works by altering cellular metabolism in a way that prevents activation of regions of the genome that should remain inactive. [Emphasis added.]

Their work showed that p53 is an epigenetic regulator: it silences genes that should not be translated during mitosis by locking them into heterochromatin. Without this control, genes become accessible to the translation machinery at the wrong time, such as during mitosis. “It causes so much damage,” they found, “that it will drive cells into a state of genomic instability that promotes and worsens cancer progression.”

“By unraveling this mechanism, we could demonstrate that there is a link between metabolism, epigenetic integrity and genomic stability. Additionally, we have demonstrated that p53 represents the switch controlling the on/off state of this protection system in response to environmental stresssums up Amelio.

The question of how p53-inactivated tumors develop genomic instability has preoccupied the scientific community for some time. “We are now certain that in these tumors there is a problem at the metabolic level which is reflected in the integrity of the epigenome. Therefore, p53 should actually be called the guardian of the (epi-)genome.

Epigenetics compacts genes into gametes

The John Innes Center in the UK has announced the solution to a puzzle: how plants pack their DNA into sperm. Animals, which have free-swimming sperm, do this by replacing their histones with protamines. But plants, which propagate their gametes via pollen, retain their histone-based chromatin through fertilization. Why the difference and how do plants compact the DNA of male gametes?

The answer was found by a Center research team led by Professor Xiaoqi Feng. These are condensates (see my article on the Caltech study) which form, by phase separation, intrinsically disordered regions of certain proteins, and epigenetics. “Professor Feng’s research team used super-resolution microscopy, comparative proteomics, single cell type epigenomic sequencing and 3D genome mapping to investigate this mystery.” Key to the solution was the identification of a histone variant named H2B.8. It is specifically expressed in sperm nuclei.

H2B.8 has a long intrinsically disordered region (IDR)a characteristic that frequently allows proteins to undergo Phase separation. Research has found that almost all species of flowering plants have H2B.8 homologs (copies), all of which contain an IDR, suggesting important functions.

So why do plants need DNA compaction, while sperm don’t need to swim to the egg? The pollen grains land on a pistil and send out long pollen tubes to reach the eggs. Sperm compaction therefore serves a purpose for angiosperms. Interestingly, gymnosperms, which use a different pollination method, do not compact their sperm genomes and lack H2B.8.

Dr Toby Buttress, first author of the study, said: “We propose that H2B.8 is an evolutionary innovation of flowering plants who reaches a moderate level of nuclear condensation compared to protamines, which sacrifice transcription for super compaction. H2B.8-mediated condensation is sufficient for immobile sperm and consistent with gene activity.

Epigenetics rules the office

A lively follow-up to Caltech’s findings last year on condensate was published by Nature, “The Shape-Changing Droplets That Shook Cell Biology.” Journalist Elie Dolgin calls these membraneless organelles droplets, condensates and granules. It uses the same office floor plan metaphor that Caltech used:

For years, if you asked a scientist how he imagined the inner workings of a cell, he might have told you about a very organized factorywith different departments each performing specialized tasks in delineated assembly lines.

Ask now, and they might be more inclined to compare the cell to a chaotic open-plan office.with hot desk areas where different types of cellular matter bring together to complete a task and then disperse to other regions.

The image is less of robots anchored to the ground on an assembly line, and more of intelligent actors coming together on the fly, interacting, sharing materials and solving problems. Isn’t it like squishy biology anyway? The cells look like chaotic spots on one level, but they somehow give rise to a flying owl, a leaping dolphin, and a mathematician in front of a blackboard. Clearly things are working at levels of engineering beyond our current ability to comprehend.

“We have the observations that form condensates,” says Jonathon Ditlev, a cell biophysicist at the Hospital for Sick Children in Toronto, Canada. “Now we have to show why they matter.”

Dolgin tells how these “blobs” self-organize by phase separation, but many questions remain. How do the right ingredients get into these “molecular crucibles” that accelerate interactions by orders of magnitude? How do they separate once the job is done? He doesn’t mention epigenetics in his article, but the implication is clear that genetics alone cannot explain this.

Epigenetics challenges evolution

Whether plant DNA compaction qualifies as an “evolutionary innovation” as opposed to an engineered solution is debatable. Regarding this controversy, Jhe scientistKatarina Zimmer asks: “Do epigenetic changes influence evolution?

Evidence is mounting that epigenetic marks on DNA may influence future generations in various ways. But how such phenomena might affect large-scale evolutionary processes is hotly debated..

After recounting a case where nematodes inherited a stress response, Zimmer delves into the current “fierce debate” between believers and skeptics over whether epigenetics requires revisions to the theory of evolution.

No one doubts the examples of epigenetic inheritance, but some in the old guard cast them for minor roles in long-term evolution. Zimmer mentions the buzz generated by Stephen Buranyi’s article at The Guardian ask, “Do we need a new theory of evolution? (see David Klinghoffer’s analysis here). One of the revisionists cited by Zimmer is Alyson Ashe of the University of Sydney, who has also observed epigenetic inheritance in C.elegans.

Specifically, the modern synthesis developed in the 1940s assumes that evolution is driven solely by random DNA mutations. While many scientists wonder whether non-DNA-based mechanisms could contribute significantly to evolutionary processes, some say the textbooks need to be updated.

“We don’t need to rewrite and throw away current theories, but they are incompleteAshe says. “They need tweaks to show how epigenetics may interact with these theories.”

Epigenetics makes the group play

Zimmer leaves the controversy unresolved, but it’s likely that Darwinians will have to deal with epigenetic music as soon as his drumbeat gets louder. If the instrumentalists are like the genes, other entities must tell the band members what music to play, when to start, and how to disperse and reassemble in the next field formation, otherwise there will be cacophony. If neo-Darwinism can’t even get random notes on a page to come up with a melody, how can it account for a drum major, a manager, a librarian, a programmer, a drill crew and all the other entities necessary for consistent performance? Using epigenetics, all players condense into the correct positions, move while playing, and deliver a performance that pleases the “Strike Up the Band” crowd.


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