Stem cells and cancer cells have enough molecular similarities that the former can be used to trigger immunity against the latter.
Scientists show how roundworm daughter cells remember the histone modification patterns of their parents.
September 18, 2014|
LAURA GAYDOSAfter DNA replication and division, cells generally remember which of their genes should be active and which repressed—but how? A study in worms published today (September 18) in Science reveals that part of the mechanism involves divvying up modified histones—molecular tags that label active or repressed genes—between daughter chromosomes at replication. Researchers from the University of California, Santa Cruz and Indiana University, Bloomington, found that although the tags in each chromosome are reduced as a result of division, subsequent recruitment of histone-modifying enzymes reestablishes the full tag quota, thus preserving the memory of modifications for the next round of division.
“They show very elegantly using their system that modified histones can be inherited through multiple rounds of cell division and can be passed on . . . to the next generation,” said Shiv Grewal, an epigenetics and chromatin researcher at the National Cancer Institute who was not involved in the work. “That’s quite remarkable.”
Histones, the proteins around which DNA is wrapped to form chromatin, can be modified by the addition a various moieties. And such modifications are thought to represent—and even influence—the transcriptional activity of associated genes. Although the presence of these modifications at given genomic locations can be inherited from a parent cell to its daughters, exactly how this landscape of histone modifications is reestablished after DNA replication—when the histones are temporarily evicted from DNA—was unclear.
“There’s been a lot of debate about whether histone modifications can be heritable,” said Bill Kelly, a biologist at Emory University in Atlanta, Georgia, who was not involved in the study. “When you replicate the DNA you have to replicate the histones . . . and de novo synthesized histones don’t have marks put there by transcription or repression,” he explained.
There have been two theories as to how histone modification patterns might be remembered, said Santa Cruz’s Susan Strome, the professor of molecular, cell, and developmental biology who led the new study. One theory suggests “histone modifications on the original mother chromosome get split between the two daughter chromosomes and probably diluted,” she said. An opposing theory, however, suggests “histone modifications are not passed through DNA replication. . . [Instead], the enzyme is passed on and it restores modifications on the two daughter chromosomes.”
Luckily, said Strome, she and her colleagues “were in a position to directly test those two models.” Her team generated Caenorhabditis elegans eggs that lacked an enzyme called Polycomb repressive complex 2 (PRC2), a histone-modifying enzyme that methylates lysine 27 of histone H3 (H3K27me)—a mark associated with transcriptional repression. Fusing these roundworm eggs with wild-type sperm resulted in a single-celled embryo with one set of chromosomes (paternal) dusted with H3K27me marks, and another (maternal) that was not. Because the sperm cannot contribute PRC2 itself, the embryos lacked the enzyme altogether, allowing Strome and colleagues to clearly visualize the fate of the existing H3K27me marks.
With each cell division the H3K27me marks became dimmer until, by approximately the 48-cell stage, they were “below the detection of the microscope,” said Strome. But, importantly, what the researchers could see was that, “histone modifications are indeed passed to the daughter chromosomes—the chromosomes derived from the initial sperm chromosomes—and the oocyte chromosomes, which did not have the mark to begin with, do not acquire it,” she added.
The team then performed a reverse experiment in which the male chromosomes were unmarked and the oocytes contained both H3K27me marks and PRC2. This time the signal did not become dimmer with each division, because PRC2 was able to reestablish the mark. But, said Strome, “what was really remarkable for us to see was that, even with active enzyme, the H3K27me marking was restricted to the parent-of-origin chromosome.” This ability to recreate marks only at their original chromosome locations was, said Strome, “the hallmark of memory.”
According to Kelly, the results suggest “that after replication there is sufficient information there that it can be targeted by the maintenance system”—the histone-modifying enzymes. Indeed, the mammalian PRC2 is capable of both binding to H3K27me as well as creating the mark, explained Strome.
The findings have implications not only for cellular inheritance of epigenetic marks but also transgenerational inheritance, which “a lot of people suspect,” said Grewal, but for which “there is not much evidence.” Indeed, added Strome: “We’re starting to get a molecular handle on what it means to pass epigenetic information from parent to child—both at the organism and cell level—and our work provides a little window into that.”
L.J. Gaydos et al., “H3K27me and PRC2 transmit a memory of repression across generations and during development,” Science, 345:1515-18, 2014.
September 19, 2014
Strike three, your theories are out.
Does anyone think this latest addition of experimental evidence is not just another thinly-veiled attempt to continue the fight against disease?
I could be wrong. Has someone else shown how mutations and natural selection lead to the evolution of biodiversity via an evolutionary event that has not been described?
If not, these results seem to support other experimental evidence of RNA-mediated cell type differentiation via amino acid substitutions in cells of individuals of all other species from microbes to man.
Will we next see a serious scientist like Eugene Koonin step in and ask how species diversity arises via mutations in the absence of cell type differentiation that leads to concurrent changes in morphological and behavioral phenotypes? See for example: A universal trend of amino acid gain and loss in protein evolution and Genomes in turmoil: Quantification of genome dynamics in prokaryote supergenomes.
If RNA-mediated events and Genome Dynamics Events are the same thing in species from microbes to man, the likelihood that evolutionary theorists will describe an evolutionary event that links mutations and/or natural selection to the evolution of biodiversity is reduced even further to what may be a statistically impossible event.
Mutations can be linked to pathology but cannot be linked to increasing organismal complexity via perturbed protein folding at the same time that amino acid substitutions stabilize the DNA in organized genomes.
Can anyone else "...conceive of a global external factor that could cause... parallel evolution of amino acid compositions of proteins in 15 diverse taxa that represent all three domains of life and span a wide range of lifestyles and environments." I think what everyone continues to show with their experimental evidence is that ecological variation leads to ecological adaptations via nutrient-dependent pheromone-controlled RNA-mediated events.
That's not evolution; is it?
September 19, 2014
@Commenter ("Posts: 0"): In my view the article apparently refers to the origin of variation in members of a population that can be transmitted to subsequent generations specifically via the (female-parent) germline as affected by its history.
What is transmitted is essentially the _effect_ of an organism's experience in its environment that causes epigenetic modification on the histone H3 tail at location K27 with a single methylation (H3K27me). The (An?) agent in this case is an enzyme called Polycomb repressive complex 2 (PRC2), but notice that it is a localized _population_ of molecules -- a complex -- that comprises proteins and one or more RNAs. In transmitting the modified histone alone, the effect decayed over F-generations. However, when transmitting PRC2 the effect not only persisted in subsequent gens, but endured robustly on the female chromo.
Notice that, as a single germline's epigenetic change, the variation doesn't pervade the population. However, if combined with other (germline) genotypes with related epigentic variation, the effect could alter subsequent generations accordingly and (leaping ahead) lead to a adaptation reflected in modified DNA in the population (evo).
The idea here is that the individual _proposes_ (variation), its population _disposes_.
Now, where does this leave the "random" DNA change assumed to produce variation? Answering that question requires placing DNA in its proper context of biological function: DNA crucially determines the specific kinds of elements produced within and constituting the specifc organism type and, retrospectively, reveals the molecular effects of the organism type's history; but DNA does not and cannot "control" organism development and physiology (critical DNA errors are repaired). The reason is that all the 'heavy lifting' and "control" occur through the dynamics of the (functionally heterogeneous) populations across all length scales of organisms, their constituent cells, tissues, organs, and populations (ecosystems) due to the inducements of their local _environments_ over time as we see in this PRC2 example. (See C. Darwin.)
September 27, 2014
Please, do not forget the unseen wireless paternal and maternal mitochondria influence in DNA replication, explained in "Mitochondrial Adam DNA data transmissions theory - ISBN 978-606-92107-1-0"