The power of epigenetic processes over genes continues to be a big subject in biology. Epigenetic processes control which genes are translated and which are silenced, which concentrations of transcripts are required, and how molecular machines assemble at the right times and places to steer gene products to their operational destinations. If sheet music is an argument for design, how much more the organization that makes it come alive in a marching band’s halftime show?
The Guardian of the Epigenome
The p53 protein has long been called the “guardian of the genome” for its key role in tumor suppression. Now, some German researchers are calling it “the guardian of the (epi)genome.” News from the University of Konstanz tells how a research team led by Ivano Amelio took a painstaking look at how p53 works.
Cells — and their DNA integrity — are particularly at risk when they divide, as they duplicate their DNA in the process. “Like in any other replication process, such as photocopying a document or copying a digital file, it is disastrous if the template moves or is changed while the copy is being made. For this reason, genes cannot be transcribed – i.e. used as templates for proteins – while the DNA is being copied,” Amelio explains. If they are transcribed anyway, serious disruptions occur, which can lead to cancer-promoting mutations. The results from Amelio and his team, now appearing as the cover story in Cell Reports, show that p53 inactivation favours such copy-related damage. They found that p53 normally acts by changing cell metabolism in a way that prevents activation of genome regions that should remain inactive. [Emphasis added.]
Their work found that p53 is an epigenetic regulator: it keeps genes silent that should not be translated during mitosis by locking them away in heterochromatin. Without this control, genes become accessible to translation machinery at the wrong time, such as during mitosis. “This causes so much damage,” they found, “that it will drive cells into a state of genomic instability that favours and worsens cancer progression.”
“By unravelling this mechanism, we could demonstrate that there is a link between metabolism, epigenetic integrity and genomic stability. In addition, we provided evidence that p53 represents the switch controlling the on/off status of this protection system in the response to environmental stress,” Amelio summarizes the finding.
The question of how p53-inactivated tumours develop genomic instability has plagued the scientific community for quite some time. “Now we have certainty that, in these tumours, there is a problem at the metabolic level that is reflected in the integrity of the epigenome. Hence, p53 should actually be called guardian of the (epi-)genome.
Epigenetics Compacts Genes in Gametes
The John Innes Centre in the UK announced the solution to an enigma: how plants compact their DNA in sperm cells. Animals, which have swimming sperm cells, do it by replacing their histones with protamines. But plants, which spread their gametes via pollen, maintain their histone-based chromatin through fertilization. Why the difference, and how do plants compact the DNA in the male gametes?
The answer was found by a research team at the Centre led by Professor Xiaoqi Feng. It involves condensates (see my article on the Caltech study) that 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 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 feature that frequently allows proteins to undergo phase separation. The research found nearly all flowering plant species have H2B.8 homologs (copies), all of which contain an IDR, suggesting important functions.
So why do plants need DNA compaction, when the sperm don’t need to swim to the egg? Pollen grains land on a pistil and send long pollen tubes to reach the eggs. Compaction of the sperm cells, therefore, serve a purpose for angiosperms. Interestingly, gymnosperms, which use a different method of pollination, 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 a flowering plant evolutionary innovation that achieves a moderate level of nuclear condensation compared to protamines, which sacrifice transcription for super compaction. H2B.8-mediated condensation is sufficient for immotile sperm and compatible with gene activity.”
Epigenetics Runs the Office
A lively follow-up to Caltech’s findings last year about condensates was published by Nature, “The shape-shifting blobs that shook up cell biology.” Reporter Elie Dolgin calls these membraneless organelles droplets, condensates, and granules. She uses the same office floor plan metaphor that Caltech used:
For years, if you asked a scientist how they pictured the inner workings of a cell, they might have spoken of a highly organized factory, with 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-desking zones where different types of cellular matter gather to complete a task and then scatter to other regions.
The picture is less one of robots anchored to the floor on an assembly line, and more one of intelligent actors gathering on the fly, interacting, sharing materials, and solving problems. Isn’t that just like squishy biology anyway? Cells seem like chaotic blobs at one level, but they somehow give rise to a flying owl, a leaping dolphin, and a mathematician at a chalkboard. Clearly things are working at levels of engineering beyond our current ability to fathom.
“We have the observations that condensates form,” says Jonathon Ditlev, a cellular biophysicist at the Hospital for Sick Children in Toronto, Canada. “Now we need to show why they are important.”
Dolgin relates how these “blobs” self-organize through phase separation, but many questions remain. How do the right ingredients get into these “molecular crucibles” that speed up interactions by orders of magnitude? How do they separate when the work 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 can be called an “evolutionary innovation” as opposed to a designed solution can be debated. Regarding that controversy, at The Scientist, Katarina Zimmer asks, “Do Epigenetic Changes Influence Evolution?”
Evidence is mounting that epigenetic marks on DNA can influence future generations in a variety of ways. But how such phenomena might affect large-scale evolutionary processes is hotly debated.
After telling about a case where nematodes inherited a stress response, Zimmer delves into the current “fierce debate” between believers and doubters about whether epigenetics requires revisions to evolutionary theory.
No one doubts the examples of epigenetic inheritance, but some in the old guard consign them to minor roles in long-term evolution. Zimmer mentions the buzz generated by the article by Stephen Buranyi at The Guardian asking, “Do we need a new theory of evolution?” (see David Klinghoffer’s analysis here). One of the revisionists Zimmer quotes is Alyson Ashe at the University of Sydney, who also observed epigenetic inheritance in C. elegans.
Specifically, the Modern Synthesis developed in the 1940s supposes that evolution is driven solely by random DNA mutations. While many scientists question whether non-DNA-based mechanisms could be meaningful contributors to evolutionary processes, some say that textbooks are due for an update.
“We don’t need to rewrite and throw away the current theories, but they’re incomplete,” says Ashe. “They need adjustment to show how epigenetics can interplay with those theories.”
Epigenetics Makes the Band Play
Zimmer leaves the controversy unresolved, but it’s likely that Darwinians will have to face the epigenetic music soon as its drumbeat gets louder. If the instrumentalists are like the genes, other entities must be telling the band members what music to play, when to start, and how to scatter and gather into the next formation on the field, or else there would be cacophony. If neo-Darwinism cannot even get random notes on a page to result in a melody, how can it account for a drum major, manager, librarian, programmer, drill team and all the other entities needed for a coherent performance? Thanks to epigenetics, all the players condense in the right positions, move around while playing, and give a crowd-pleasing performance of “Strike Up the Band.”