GN/ Unveiling the mechanism guiding the evolution of multicellular life
Genetics biweekly vol.53, 4th March — 21st March
TL;DR
- Researchers uncover mechanism guiding multicellular evolution via altered protein folding.
- Team deciphers complex genetic diversity mechanism.
- Protein enabling mammalian cold sensation finally identified.
- Retinoic acid, the active state of Vitamin A, appears to regulate stem cell behavior in wound repair.
- Artificial nucleotides with enhanced properties synthesized for the first time.
- Improved method for observing cell interactions promises comprehensive mapping.
- Genomic imprinting linked to parental gene expression inheritance explained.
- Computational model sheds light on virus structure and DNA dynamics.
- Breakthrough in understanding DNA copying machine’s role in passing epigenetic information.
- Gene enabling unique chlorophyll production in marine algae implanted in land plants for enhanced crop yields.
- And more!
Overview
Genetic technology is defined as the term that includes a range of activities concerned with the understanding of gene expression, advantages of natural genetic variation, modifying genes and transferring genes to new hosts. Genes are found in all living organisms and are transferred from one generation to the next. Gene technology encompasses several techniques including marker-assisted breeding, RNAi, and genetic modification. Only some gene technologies produce genetically modified organisms.
Modern genetic technologies like genome editing would not be possible without all the previous generations of genetic technologies that have enabled scientists to discover what genes are, what they do, and how DNA can be modified to add, remove, or replace genes. You can find major genetic technologies development milestones via the link.
Gene Technology Market
- The valuation of the genetic engineering market is projected to escalate to USD 6.90 MN by the end of 2027.
- Global Genetic Engineering Market is projected to grow at 12.48% CAGR during the assessment period (2017–2027).
- North America holds the largest share of the global genetic engineering market, followed by Europe and the Asia Pacific, respectively.
Latest News & Research
Proteostatic tuning underpins the evolution of novel multicellular traits
by Kristopher Montrose, Dung T. Lac, Anthony J. Burnetti, Kai Tong, G. Ozan Bozdag, Mikaela Hukkanen, William C. Ratcliff, Juha Saarikangas in Science Advances
Researchers have discovered a mechanism steering the evolution of multicellular life. They identified how altered protein folding drives multicellular evolution.
In a new study led by researchers from the University of Helsinki and the Georgia Institute of Technology, scientists turned to a tool called experimental evolution. In the ongoing Multicellularity Long Term Evolution Experiment (MuLTEE), laboratory yeast are evolving novel multicellular functions, enabling researchers to investigate how they arise. The study puts the spotlight on the regulation of proteins in understanding evolution.
“By demonstrating the effect of protein-level changes in facilitating evolutionary change, this work highlights why knowledge of the genetic code in itself does not provide a full understanding of how organisms acquire adaptive behaviors. Achieving such understanding requires mapping the entire flow of genetic information, extending all the way to the actionable states of proteins that ultimately control the behavior of cells,” says Associate Professor Juha Saarikangas from the Helsinki Institute of Life Science HiLIFE and Faculty of Biological and Environmental Sciences, University of Helsinki.
Among the most important multicellular innovations is the origin of robust bodies: over 3,000 generations, these ‘snowflake yeast’ started out weaker than gelatin but evolved to be as strong and tough as wood. Researchers identified a non-genetic mechanism at the base of this new multicellular trait, which acts at the level of protein folding. The authors found that the expression of the chaperone protein Hsp90, which helps other proteins acquire their functional shape, was gradually turned down as snowflake yeast evolved larger, tougher bodies. It turns out Hsp90 acted as a critically-important tuning knob, destabilizing a central molecule that regulates the progression of the cell cycle, causing cells to become elongated. This elongated shape, in turn, allows cells to wrap around one another, forming larger, more mechanically tough multicellular groups.
“Hsp90 has long been known to stabilize proteins and help them fold properly,” explains lead author Kristopher Montrose, from the Helsinki Institute of Life Science, Finland. “What we’ve found is that slight alterations in how Hsp90 operates can have profound effects not just on single cells, but on the very nature of multicellular organisms.”
From an evolutionary perspective, this work highlights the power of non-genetic mechanisms in rapid evolutionary change.
“We tend to focus on genetic change and were quite surprised to find such large changes in the behavior of chaperone proteins. This underscores how creative and unpredictable evolution can be when finding solutions to new problems, like building a tough body.,” says Professor Will Ratcliff from the Georgia Institute of Technology, USA.
Control of meiotic crossover interference by a proteolytic chaperone network
by Heejin Kim, Jaeil Kim, Namil Son, Pallas Kuo, Chris Morgan, Aurélie Chambon, Dohwan Byun, Jihye Park, Youngkyung Lee, Yeong Mi Park, John A. Fozard, Julie Guérin, Aurélie Hurel, Christophe Lambing, Martin Howard, Ildoo Hwang, Raphael Mercier, Mathilde Grelon, Ian R. Henderson, Kyuha Choi in Nature Plants
Movies such as ‘X-Men,’ ‘Fantastic Four,’ and ‘The Guardians,’ which showcase vibrant mutant heroes, have captivated global audiences. Recently, a high-throughput genetic screening of meiotic crossover rate mutants in Arabidopsis thaliana garnered the interest of the academic community by unraveling a century-old mystery in the life sciences.
A research team, consisting of Professor Kyuha Choi, Dr. Jaeil Kim, and PhD candidate Heejin Kim from the Department of Life Sciences at Pohang University of Science and Technology (POSTECH), has achieved a remarkable feat by unveiling the molecular mechanism responsible for crossover interference during meiosis, a biological pattern at the chromosome level.
In sexually reproducing organisms, individuals resemble their parents or siblings. Despite the striking similarities, it’s crucial to recognize that absolute identicalness is unattainable. This variation is attributed to the process of meiosis, which generates reproductive cells like sperm and eggs in animals or pollen and ovules in plants. Unlike somatic cell division, which duplicates and divides the genome identically, meiosis creates genetically diverse reproductive cells through a mechanism known as crossover.
Meiosis and crossover play pivotal roles in biodiversity and have significant implications in breeding where the selection and cultivation of superior traits in crops occur. Typically, most animal and plant species exhibit a minimum of one and a maximum of three crossovers per a pair of homologous chromosomes. The ability to control the number of these crossovers could lead to cultivating crops with specific desired traits. However, achieving such control has been challenging due to the ‘phenomenon of crossover interference.’ Crossover interference, where one crossover inhibits the formation of another crossover nearby along the same chromosome, was initially identified by fruit fly geneticist Hermann J. Muller in 1916. Despite researchers’ persistent efforts over the past century since its discovery, it is only recently that the mechanisms underlying crossover interference have started to unveil their secrets.
In this research, the team utilized a high-throughput fluorescent seed scoring method to directly measure crossover frequency in Arabidopsis plants. Through a genetic screen, they identified a mutant named hcr3 (high crossover rate3) that exhibited an increased crossover rate at the genomic level. Further analysis revealed that the elevated crossovers in hcr3 was attributed to a point mutation in the J3 gene, which encodes a co-chaperone related to HSP40 protein. This research demonstrated that a network involving HCR3/J3/HSP40 co-chaperone and the chaperone HSP70 controls crossover interference and localization by facilitating the degradation of the pro-crossover protein, HEI10 ubiquitin E3 ligase. The application of genetic screen approaches to uncover the crossover interference and inhibition pathway successfully addressed a century-old puzzle in the life sciences.
POSTECH Professor Kyuha Choi stated, “Applying this research to agriculture will enable us to rapidly accumulate beneficial traits, thereby reducing breeding time.” He expressed optimism by saying, “We hope this research will contribute to the breeding of new varieties and identification of useful natural variations responsible for desirable traits such as disease and environmental stress resistance, improved productivity, and high-value production.”
The kainate receptor GluK2 mediates cold sensing in mice
by Wei Cai, Wenwen Zhang, Qin Zheng, Chia Chun Hor, Tong Pan, Mahar Fatima, Xinzhong Dong, Bo Duan, X. Z. Shawn Xu in Nature Neuroscience
University of Michigan researchers have identified the protein that enables mammals to sense cold, filling a long-standing knowledge gap in the field of sensory biology.
The findings could help unravel how we sense and suffer from cold temperature in the winter, and why some patients experience cold differently under particular disease conditions.
“The field started uncovering these temperature sensors over 20 years ago, with the discovery of a heat-sensing protein called TRPV1,” said neuroscientist Shawn Xu, a professor at the U-M Life Sciences Institute and a senior author of the new research.
“Various studies have found the proteins that sense hot, warm, even cool temperatures — but we’ve been unable to confirm what senses temperatures below about 60 degrees Fahrenheit.”
In a 2019 study, researchers in Xu’s lab discovered the first cold-sensing receptor protein in Caenorhabditis elegans, a species of millimeter-long worms that the lab studies as a model system for understanding sensory responses. Because the gene that encodes the C. elegans protein is evolutionarily conserved across many species, including mice and humans, that finding provided a starting point for verifying the cold sensor in mammals: a protein called GluK2 (short for Glutamate ionotropic receptor kainate type subunit 2).
For this latest study, a team of researchers from the Life Sciences Institute and the U-M College of Literature, Science, and the Arts tested their hypothesis in mice that were missing the GluK2 gene, and thus could not produce any GluK2 proteins. Through a series of experiments to test the animals’ behavioral reactions to temperature and other mechanical stimuli, the team found that the mice responded normally to hot, warm and cool temperatures, but showed no response to noxious cold.
GluK2 is primarily found on neurons in the brain, where it receives chemical signals to facilitate communication between neurons. But it is also expressed in sensory neurons in the peripheral nervous system (outside the brain and spinal cord).
“We now know that this protein serves a totally different function in the peripheral nervous system, processing temperature cues instead of chemical signals to sense cold,” said Bo Duan, U-M associate professor of molecular, cellular, and developmental biology and co-senior author of the study.
While GluK2 is best known for its role in the brain, Xu speculates that this temperature-sensing role may have been one of the protein’s original purposes. The GluK2 gene has relatives across the evolutionary tree, going all the way back to single-cell bacteria.
“A bacterium has no brain, so why would it evolve a way to receive chemical signals from other neurons? But it would have great need to sense its environment, and perhaps both temperature and chemicals,” said Xu, who is also a professor of molecular and integrative physiology at the U-M Medical School. “So I think temperature sensing may be an ancient function, at least for some of these glutamate receptors, that was eventually co-opted as organisms evolved more complex nervous systems.”
In addition to filling a gap in the temperature-sensing puzzle, Xu believes the new finding could have implications for human health and well-being. Cancer patients receiving chemotherapy, for example, often experience painful reactions to cold.
“This discovery of GluK2 as a cold sensor in mammals opens new paths to better understand why humans experience painful reactions to cold, and even perhaps offers a potential therapeutic target for treating that pain in patients whose cold sensation is overstimulated,” Xu said.
Vitamin A resolves lineage plasticity to orchestrate stem cell lineage choices
by Matthew T. Tierney, Lisa Polak, Yihao Yang, Merve Deniz Abdusselamoglu, Inwha Baek, Katherine S. Stewart, Elaine Fuchs in Science
Retinoic acid, the active state of Vitamin A, appears to regulate how stem cells enter and exit a transient state central to their role in wound repair.
When a child falls off her bike and scrapes her knee, skin stem cells rush to the rescue, growing new epidermis to cover the wound. But only some of the stem cells that will ultimately patch her up are normally dedicated to replenishing the epidermis that protects her body. Others are former hair follicle stem cells, which usually promote hair growth but respond to the more urgent needs of the moment, morphing into epidermal stem cells to bolster local ranks and repair efforts. To do that, these hair follicle stem cells first enter a pliable state in which they temporarily express the transcription factors of both types of stem cells, hair and epidermis.
Now, new research demonstrates that once stem cells have entered this state, known as lineage plasticity, they cannot function effectively in either role until they choose a definitive fate. In a screen to identify key regulators of this process, retinoic acid, the biologically active form of Vitamin A, surfaced as a surprising rheostat. The findings shed light on lineage plasticity, with potential clinical implications.
“Our goal was to understand this state well enough to learn how to dial it up or down,” says Rockefeller’s Elaine Fuchs. “We now have a better understanding of skin and hair disorders, as well as a path toward preventing lineage plasticity from contributing to tumor growth.”
Lineage plasticity has been observed in multiple tissues as a natural response to wounding and an unnatural feature of cancer. But minor skin injuries are the best place to study the phenomenon, because the skin’s outer layers are subject to perpetual abuse. And when the scratches or abrasions damage the epidermis, hair follicle stem cells are the first responders.
Fuchs and colleagues began to look more closely at lineage plasticity because it, “can act as a double edged sword,” explains Matthew Tierney, lead author on the paper and an NIH K99 “pathway to independence” postdoctoral awardee in the Fuchs lab. “The process is necessary to redirect stem cells to parts of the tissue most in need but, if left unchecked, it can leave those same tissues vulnerable to chronic states of repair and even some types of cancer.”
To better understand how the body regulates this process, Fuchs and her team screened small molecules for their ability to resolve lineage plasticity in cultured mouse hair follicle stem cells, under conditions that mimicked a wound state. They were surprised to find that retinoic acid, a biologically active form of vitamin A, was essential for these stem cells to exit lineage plasticity and then be coaxed to differentiate into hair cells or epidermal cells in vitro.
“Through our studies, first in vitro and then in vivo, we discovered a previously unknown function for vitamin A, a molecule that has long been known to have potent but often puzzling effects on skin and many other organs,” Fuchs says.
The team found that genetic, dietary, and topical interventions that boosted or removed retinoic acid from mice all confirmed its role in balancing how stem cells respond to skin injuries and hair regrowth. Interestingly, retinoids did not operate on their own: their interplay with signaling molecules such as BMP and WNT influenced whether the stem cells should maintain quiescence or actively engage in regrowing hair.
The nuance did not stop there. Fuchs and colleagues also demonstrated that retinoic acid levels must fall for hair follicle stem cells to participate in wound repair — if levels are too high, they fail to enter lineage plasticity and can’t repair wounds — but if the levels are too low, the stem cells focus too heavily on wound repair, to the expense of hair regeneration.
“This may be why vitamin A’s effects on tissue biology have been so elusive,” Fuchs says.
One result of retinol biology remaining obscure for so long is that retinoid and vitamin A applications have long produced confusing results. Topical retinoids are known to stimulate hair growth in wounds, but excessive retinoids have been shown to prevent hair cycling and cause alopecia; both positive and negative effects of retinoids on epidermal repair have been documented through various studies. The present study bringd greater clarity by casting retinoids in a more central role — at the helm of regulating both hair follicle and epidermal stem cells.
“By defining the minimal requirements needed to form mature hair cell types from stem cells outside the body, this work has the potential to transform the way we approach the study of hair biology,” Tierney says.
How retinoids impact other tissues remains to be seen. “When you eat a carrot, vitamin A gets stored in the liver as retinol where it is sent to various tissues,” Fuchs says. “Many tissues that receive retinol and convert it to retinoic acid need wound repair and use lineage plasticity, so it will be interesting to see how broad the implications of our findings in skin will be.”
The Fuchs lab is also interested in how retinoids impact lineage plasticity in cancer, particularly squamous and basal cell carcinoma. “Cancer stem cells never make the right choice — they are always doing something off-beat,” Fuchs says. “As we were studying this state in many types of stem cells, we began to realize that, when lineage plasticity goes unchecked, it’s a key contributor to cancer.”
Basal cell carcinomas have relatively little lineage plasticity and are far less aggressive than squamous cell carcinomas. If future studies demonstrate that suppressing lineage plasticity is key to controlling tumor growth and improving outcomes, retinoids may have a key role to play in treating these cancers.
“It’s possible that suppressing lineage plasticity can improve prognoses,” Fuchs says. “This hasn’t been on the radar until now. It’s an exciting front to now investigate.”
Expanding the Horizon of the Xeno Nucleic Acid Space: Threose Nucleic Acids with Increased Information Storage
by Hannah Depmeier, Stephanie Kath-Schorr in Journal of the American Chemical Society
The DNA carries the genetic information of all living organisms and consists of only four different building blocks, the nucleotides. Nucleotides are composed of three distinctive parts: a sugar molecule, a phosphate group and one of the four nucleobases adenine, thymine, guanine and cytosine. The nucleotides are lined up millions of times and form the DNA double helix, similar to a spiral staircase. Scientists from the UoC’s Department of Chemistry have now shown that the structure of nucleotides can be modified to a great extent in the laboratory.
The researchers developed so-called threofuranosyl nucleic acid (TNA) with a new, additional base pair. These are the first steps on the way to fully artificial nucleic acids with enhanced chemical functionalities.
Artificial nucleic acids differ in structure from their originals. These changes affect their stability and function. “Our threofuranosyl nucleic acid is more stable than the naturally occurring nucleic acids DNA and RNA, which brings many advantages for future therapeutic use,” said Professor Dr Stephanie Kath-Schorr.
For the study, the 5-carbon sugar deoxyribose, which forms the backbone in DNA, was replaced by a 4-carbon sugar. In addition, the number of nucleobases was increased from four to six. By exchanging the sugar, the TNA is not recognized by the cell’s own degradation enzymes. This has been a problem with nucleic acid-based therapeutics, as synthetically produced RNA that is introduced into a cell is rapidly degraded and loses its effect. The introduction of TNAs into cells that remain undetected could now maintain the effect for longer.
“In addition, the built-in unnatural base pair enables alternative binding options to target molecules in the cell,” added Hannah Depmeier, lead author of the study.
Kath-Schorr is certain that such a function can be used in particular in the development of new aptamers, short DNA or RNA sequences, which can be used for the targeted control of cellular mechanisms. TNAs could also be used for the targeted transport of drugs to specific organs in the body (targeted drug delivery) as well as in diagnostics; they could also be useful for the recognition of viral proteins or biomarkers.
Universal recording of immune cell interactions in vivo
by Sandra Nakandakari-Higa, Sarah Walker, Maria C. C. Canesso, Verena van der Heide, Aleksey Chudnovskiy, Dong-Yoon Kim, Johanne T. Jacobsen, Roham Parsa, Jana Bilanovic, S. Martina Parigi, Karol Fiedorczuk, Elaine Fuchs, Angelina M. Bilate, Giulia Pasqual, Daniel Mucida, Alice O. Kamphorst, Yuri Pritykin, Gabriel D. Victora in Nature
One of the fundamental goals of basic biology is understanding how diverse cell types work in concert to form tissues, organs, and organ systems. Recent efforts to catalog the different cell types in every tissue in our bodies are a step in the right direction, but only one piece of the puzzle. The great mystery of how those cells communicate with one another remains unsolved.
Now, a new paper describes uLIPSTIC, a tool capable of laying the groundwork for a dynamic map tracking the physical interactions between different cells — the elusive cellular interactome. The authors have been perfecting the technology since 2018 and the latest iteration can in principle allow researchers to directly observe any cell-to-cell interaction in vivo.
“With uLIPSTIC we can ask how cells work together, how they communicate, and what messages they transfer,” says Rockefeller’s Gabriel D. Victora. “That’s where biology resides.”
Ever since single-cell mRNA sequencing came into its own, researchers have been scrambling to connect the dots and explain how diverse cells unite to form tissue. Several methods of cataloging cell-to-cell interactions have already emerged, but all have considerable shortcomings. Early efforts that involved direct observation under a microscope failed to retrieve interacting cells for further analysis; subsequent attempts leaned on advanced imaging techniques that intuit how cells might interact based on their structure and proximity to other cells. No approach captured true physical interactions and signal exchange between cell membranes.
Enter LIPSTIC, an innovative approach from the Victora lab that involved labeling cellular structures that touch when two cells make fleeting, “kiss-and-run” contact before parting ways. The labels ensured that, if one cell “kissed” another, it would leave a mark akin to a lipstick, enabling easy identification and quantification of physical interactions between cells.
Originally, the platform had narrow applications. Victora and colleagues designed LIPSTIC to record a very specific kind of cell-to-cell interaction between T cells and B cells, a major focus of their lab. Other researchers, however, began clamoring for a version of LIPSTIC that would work on other cellular interactions too.
“We could have tailored a LIPSTIC for every type of interaction,” Victora says. “But why not try to make a universal version, instead?”
In the original version of LIPSTIC, a “donor” cell uses an enzyme borrowed from bacteria to place a labeled peptide tag onto the surface of an “acceptor” cell upon contact — the biochemical equivalent of applying lipstick to one cell and looking for a kiss print on another. That method required knowing exactly how the “kiss” would occur, identifying molecules the donor cell uses to interact with recipient cells and painstakingly forcing the tags onto those molecules. But over time the team discovered that dousing the cells with a high volume of enzyme and its target would ensure that any interaction that one cell had with another cell would be tracked just as efficiently.
“If you cram partner cells with enough enzyme and target, you can make any any cell pair capable of LISPTIC labeling without needing to know in advance what molecules these cells will use for their interaction,” Victora says.
The result was a uLIPSTIC, a universal platform not bound by foreknowledge of molecules, ligands, or receptors. Scientists can now theoretically smear uLIPSTIC on any cell, without preconceived notions of how it would interact with its environment, and observe physical cell-to-cell interactions. To demonstrate the power of the platform, the team showed that uLIPSTIC could expand beyond LIPSTIC’s narrow repertoire of B cells and T cells to track how dendritic cells kickstart the body’s immune response against tumors and food allergens.
“The reception to uLIPSTIC has been great,” says Sandra Nakandakari-Higa, a PhD student in the Victora lab and lead author on the paper. “We’re already getting a lot of inquiries from other labs about how they can adapt our system to their models.”
The team hopes to eventually use uLIPSTIC to discover the receptor-ligand pairs key to cellular interactions, in an effort to better understand how cells unite into tissue at the molecular level. Eventually, the team envisions uLIPSTIC as a key tool in the effort to generate comprehensive atlases describing how cells interact to form tissue — a key to the long-awaited interactome.
Selfish conflict underlies RNA-mediated parent-of-origin effects
by Pinelopi Pliota, Hana Marvanova, Alevtina Koreshova, Yotam Kaufman, Polina Tikanova, Daniel Krogull, Andreas Hagmüller, Sonya A. Widen, Dominik Handler, Joseph Gokcezade, Peter Duchek, Julius Brennecke, Eyal Ben-David, Alejandro Burga in Nature
Some of our genes can be expressed or silenced depending on whether we inherited them from our mother or our father. The mechanism behind this phenomenon, known as genomic imprinting, is determined by DNA modifications during egg and sperm production. The Burga Lab at the Institute of Molecular Biotechnology (IMBA) of the Austrian Academy of Sciences uncovered a novel gene regulation process, associated with the silencing of selfish genes, that could represent the first step in the evolution of imprinting. Alejandro Burga and his lab at IMBA, in collaboration with the lab of Eyal Ben-David at the Hebrew University, have reported the discovery of the first parent-of-origin effect in nematodes.
In diploid organisms, one set of chromosomes is inherited from each parent. However, not all of the genes contained within will be expressed equally; instead, some may be silenced depending on whether they were inherited from the mother or the father. This phenomenon, known as genomic imprinting, depends on DNA methylation, an epigenetic signal that is erased and rewritten in every generation. Genomic imprinting arose independently in mammals and plants over 100 million years ago. However, how this mechanism evolved has, so far, remained largely a mystery. Key to solving this enigma is understanding how parent-of-origin effects, the substrate for the evolution of imprinting, evolved in the first place.
Thirty years ago, Denise Barlow, a pioneer in the study of imprinting working at the IMP, also located at the Vienna BioCenter, hypothesized that imprinting could be evolutionarily related to genome defense mechanisms that silence parasitic DNA elements called selfish genetic elements. Selfish elements and the defense mechanisms against them participate in an arms race: each evolves further to outcompete the other. Although much has been discovered about selfish element silencing in the thirty years since Denise Barlow postulated her theory, a direct connection between germline defense mechanisms and the origin of parent-of-origin effects was missing. The findings by the Burga lab provide the first clear example of how parent-of-origin effects can originate from the host small RNA genome defense pathway. Their findings point to the potential evolutionary origin of imprinting.
Sometimes in science, curiosity and attention to surprising details can lead to unexpected paths and new discoveries. This was the case when first author Pinelopi Pliota was studying selfish genetic elements in a new nematode model organism called C. tropicalis, a close cousin of the more widely studied C. elegans. Pliota was investigating toxin-antidote elements (TAs), a type of selfish element that has evolved a fascinating mechanism to ensure its own inheritance: When a mother carries the TA, it will “poison” its eggs with a toxin that can only be countered by an antidote which is also present in the TA,” she explains, “this way, all descendants that don’t inherit the TA will either die or be developmentally delayed.
To generate the mothers they were studying, the group always crossed a mother C. tropicalis carrying the TA with a father not carrying it. Pinelopi asked me if we had ever done these crossings the other way around explains Alejandro Burga, corresponding author of the publication. Her curiosity led to an interesting discovery: To our surprise, this reciprocal crossing produced mothers incapable of poisoning their eggs. All of a sudden, there was no effect at all, explains Pliota. Fascinated by this unexpected result, the team decided to study how inheriting the TA from the mother or the father could lead to different effects. We wanted to understand how this happens, what the molecular basis of this parent-of-origin effect is, says Burga.
To figure out the mechanism of the observed parent-of-origin effect, the Burga group decided to study the main germline defense mechanism against selfish genetic elements, known as the piRNA pathway. In the piRNA pathway, a coordinated effort of different small RNA molecules and proteins silences the expression of selfish elements during germline development to ensure genome stability in reproduction.
The group, collaborating with the lab of Julius Brennecke, also at IMBA, were able to identify the piRNA molecules and proteins involved in silencing the toxin-antidote element. However, all these factors alone didn’t explain the parent-of-origin-specific results they were observing. The researchers were missing a piece in this puzzle.
Fortunately, the Burga group had one last trick up their sleeve: We knew from previous research that worms have evolved various ingenious ways to discriminate their own genes from foreign elements like a virus or a selfish element. Burga says.We realized that, in this case, the key missing element was maternal RNA which is loaded into eggs.
They proved that, in maternal inheritance, the TA is accompanied by the toxin mRNA, which is expressed in the germline of the mother and loaded into the egg. The Burga group showed that this mRNA marks the TA as “own,” avoiding its silencing by the piRNA pathway. This process is called epigenetic licensing, and its balance with the piRNA pathway determines whether a gene is expressed or not.
On the other hand, when the TA is inherited paternally, the lack of maternal mRNA means there is no licensing, leading to a strong repression of the toxin gene and very low levels of toxin being expressed. By default, the piRNA pathway will silence the toxin gene explains Burga. Unless there’s maternal mRNA that licenses it by repressing the piRNA pathway. This inhibition of the inhibitor is what causes the toxin gene to be active, and the eggs to be poisoned.
Interestingly, this silencing pattern was observed to last for several generations, meaning that lack of licensing in one generation can even affect their great-grand-daughters. This is not the case in genomic imprinting, which gets reset in each generation.
The results from the Burga group cement the evolutionary link between parent-specific gene expression and host defence mechanisms, tracing the origins back to organisms that lack DNA methylation and canonical imprinting. Despite the differences between these processes in worms and mammals, the Burga group believes that the mechanism they described could represent an evolutionary first step for more advanced forms of inherited silencing. These more advanced forms of silencing ended up regulating the expression of the cell’s endogenous genes, leading to the evolution of genomic imprinting.
The structure and physical properties of a packaged bacteriophage particle
by Kush Coshic, Christopher Maffeo, David Winogradoff, Aleksei Aksimentiev in Nature
A computational model of the more than 26 million atoms in a DNA-packed viral capsid expands our understanding of virus structure and DNA dynamics, insights that could provide new research avenues and drug targets, University of Illinois Urbana-Champaign researchers report.
“To fight a virus, we want to know everything there is to know about it. We know what’s inside in terms of components, but we don’t know how they’re arranged,” said study leader Aleksei Aksimentiev, an Illinois professor of physics. “Knowledge of the internal structures gives us more targets for drugs, which currently tend to focus on receptors on the surface or replication proteins.”
Viruses keep their genetic material — either DNA or RNA — packaged in a hollow particle called a capsid. While the structures of many hollow capsids have been described, the structure of a full capsid and the genetic material inside it has remained elusive. For this first look at a complete packaged viral genome, the researchers focused on HK97, a virus that infects bacteria. It has been well-studied experimentally, so the Illinois group would be able to compare its simulations to what has been found previously, said Aksimentiev, who also is affiliated with the Beckman Institute of Advanced Science and Technology at Illinois.
“We know from experiments that the capsid has a portal, and there is a motor protein there that pushes the DNA in. We also know the structure of the capsid from experiments. We know the genetic sequence, but what was not known was the structure of the packaged genetic material inside.”
Figuring out the structural dynamics of genome packaging has challenged researchers for several reasons. It cannot yet be seen experimentally, so simulation on a supercomputer is required. However, a simulation can either show great detail for a very short time, or less detail for longer time.
The Illinois group developed a multiresolution approach to DNA simulation, looking at the problem at multiple levels of resolution and time length and putting all the information together to get a more complete picture of the process. Having previously used and validated it in experiments involving DNA origami, they now applied the multiresolution approach to HK97. The result was the first atom-level look at the viral DNA packaging process and the structural properties and fluctuations when the DNA is fully contained in the capsid.
They found that the DNA formed switchback loops as it was pushed into the capsid, an important finding as it is similar to how DNA is organized in eukaryotic cells. They also found that the DNA organized itself into domains conforming to the topology of the capsid. The process resulted in slightly different configurations of loops and topologies of DNA in each particle simulated.
“These differences show that the concept of individuality is not exclusive to animals and plants but extends down to viruses, the most primitive form of gene-replicating structures,” Aksimentiev said. “This opens another dimension to looking at infectivity, and whether these differences among viruses account for variability in their ability to infect.”
The simulations did reveal common structural features and defects, particularly at the edges and corners of the capsid, where its shape has the greatest influence on the DNA inside. These features could be potential targets for drug development, Aksimentiev said.
“We believe this is just the beginning for our methodology, the first study to look at the structure of a viral genome,” Aksimentiev said. “With bigger, faster computers, and more knowledge from experiments, we will eventually be able to computationally resolve the structures of genomes from other viral species, including RNA viruses, which are more complicated as they self-assemble.”
“The more we know about these viruses, the more we can combat them, or harness them for applications such as combating bacteria that have grown resistant to antibiotic use,” Aksimentiev said.
Parental histone transfer caught at the replication fork
by Ningning Li, Yuan Gao, Yujie Zhang, Daqi Yu, Jianwei Lin, Jianxun Feng, Jian Li, Zhichun Xu, Yingyi Zhang, Shangyu Dang, Keda Zhou, Yang Liu, Xiang David Li, Bik Kwoon Tye, Qing Li, Ning Gao, Yuanliang Zhai in Nature
A research team led by Professor Yuanliang ZHAI at the School of Biological Sciences, The University of Hong Kong (HKU) collaborating with Professor Ning GAO and Professor Qing LI from Peking University (PKU), as well as Professor Bik-Kwoon TYE from Cornell University, has recently made a significant breakthrough in understanding how the DNA copying machine helps pass on epigenetic information to maintain gene traits at each cell division. Understanding how this coupled mechanism could lead to new treatments for cancer and other epigenetic diseases by targeting specific changes in gene activity.
Our bodies are composed of many differentiated cell types. Genetic information is stored within our DNA which serves as a blueprint guiding the functions and development of our cells. However, not all parts of our DNA are active at all times. In fact, every cell type in our body contains the same DNA, but only specific portions are active, leading to distinct cellular functions. For example, identical twins share nearly identical genetic material but exhibit variations in physical characteristics, behaviours and disease susceptibility due to the influence of epigenetics. Epigenetics functions as a set of molecular switches that can turn genes on or off without altering the DNA sequence. These switches are influenced by various environmental factors, such as nutrition, stress, lifestyle, and environmental exposures.
In our cells, DNA is organised into chromatin. The nucleosome forms a fundamental repeating unit of chromatin. Each nucleosome consists of approximately 147 base pairs of DNA wrapped around a histone octamer which is composed of two H2A-H2B dimers and one H3-H4 tetramer. During DNA replication, parental nucleosomes carrying the epigenetic tags, also known as histone modifications, are dismantled and recycled, ensuring the accurate transfer of epigenetic information to new cells during cell division. Errors in this process can alter the epigenetic landscape, gene expression and cell identity, with potential implications for cancer and ageing. Despite extensive research, the molecular mechanism by which epigenetic information is passed down through the DNA copying machine, called the replisome, remains unclear. This knowledge gap is primarily due to the absence of detailed structures that capture the replisome in action when transferring parental histones with epigenetic tags. Studying the process is challenging because of the fast-paced nature of chromatin replication, as it involves rapid disruption and restoration of nucleosomes to keep up with the swift DNA synthesis.
In previous studies, the research team made significant progress in understanding the DNA copying mechanism, including determining the structures of various replication complexes. These findings laid a solid foundation for the current research on the dynamic process of chromatin duplication.
This time, the team achieved another breakthrough by successfully capturing a key snapshot of parental histone transfer at the replication fork. They purified endogenous replisome complexes from early-S-phase yeast cells on a large scale and utilised cryo-electron microscopy (cryo-EM) for visualisation. They found that a chaperone complex FACT (consisting of Spt16 and Pob3) interacts with parental histones at the front of the replisome during the replication process. Notably, they observed that Spt16, a component of FACT, captures the histones that have been completely stripped off the duplex DNA from the parental nucleosome. The evicted histones are preserved as a hexamer, with one H2A-H2B dimer missing. Another protein that involved in DNA replication, Mcm2, takes the place of the missing H2A-H2B dimer on the vacant site of the parental histones, placing the FACT-histone complex onto the front bumper of the replisome engine, called Tof1. This strategic positioning of histone hexamer on Tof1 by Mcm2 facilitates the subsequent transfer of parental histones to the newly synthesised DNA strands. These findings provide crucial insights into the mechanism that regulates parental histone recycling by the replisome to ensure the faithful propagation of epigenetic information at each cell division.
This study, led by Professor Zhai, involved a collaborative effort that spanned nearly eight years, starting at HKUST and concluding at HKU. He expressed his excitement about the findings, ‘It only took us less than four months from submission to Nature magazine to the acceptance of our manuscript. The results are incredibly beautiful. Our cryo-EM structures offer the first visual glimpse into how the DNA copying machine and FACT collaborate to transfer parental histone at the replication fork during DNA replication. This knowledge is crucial for elucidating how epigenetic information is faithfully maintained and passed on to subsequent generations. But, there is still much to learn. As we venture into uncharted territory, each new development in this field will represent a big step forward for the study of epigenetic inheritance.’
The implications of this research extend beyond understanding epigenetic inheritance. Scientists can now explore gene expression regulation, development, and disease with greater depth. Moreover, this breakthrough opens up possibilities for targeted therapeutic interventions and innovative strategies to modulate epigenetic modifications for cancer treatment. As the scientific community delves deeper into the world of epigenetics, this study represents a major step towards unravelling the complexities of replication-coupled histone recycling.
Biosynthesis of chlorophyll c in a dinoflagellate and heterologous production in planta
by Robert E. Jinkerson, Daniel Poveda-Huertes, Elizabeth C. Cooney, Anna Cho, Rocio Ochoa-Fernandez, Patrick J. Keeling, Tingting Xiang, Johan Andersen-Ranberg in Current Biology
Scientists have discovered the gene that enables marine algae to make a unique type of chlorophyll. They successfully implanted this gene in a land plant, paving the way for better crop yields on less land.
Finding the gene solves a long-standing mystery amongst scientists about the molecular pathways that allow the algae to manufacture this chlorophyll and survive.
“Marine algae produce half of all the oxygen we breathe, even more than plants on land. And they feed huge food webs, fish that get eaten by mammals and humans,” said UC Riverside assistant professor of bioengineering and lead study author Tingting Xiang. “Despite their global significance, we did not understand the genetic basis for the algae’s survival, until now.”
The study also documents another first-of-its-kind achievement: demonstrating that a land plant could produce the marine chlorophyll. Tobacco plants were used for this experiment, but in theory, any land plant may be able to incorporate the marine algae gene, allowing them to absorb a fuller spectrum of light and achieve better growth.
Chlorophyll is a pigment that enables photosynthesis, the process of converting light into “food,” or chemical energy. Plants produce chlorophyll a and b, while most marine algae and kelp produce c, which enables them to absorb the blue-green light that reaches the water.
“Chlorophylls b and c absorb light at different wavelengths,” said Xiang. “The ocean absorbs red light, which is why it looks blue. Chlorophyll c evolved to capture the blue-green light that penetrates deeper into the water.”
An additional application of this research could be in the production of algae biofuels. There are a few algae species that produce chlorophylls a or b like land plants, instead of c. Imbuing those algae with the gene to make chlorophyll c could also enhance their ability to use more light and increase their growth, creating more feedstock for the fuels.
The researchers initially set out to gain insight into an algae species that lives in coral. These algae manufacture sugars and share them with their coral hosts. “Each coral colony has thousands of polyps, and their brown color is from the algae. Whenever you see coral bleaching, it’s due to the loss of the algae,” Xiang said.
Interested in how the algae’s ability to do photosynthesis would affect the coral, the researchers worked with mutant algae as an experiment. These rare mutants were more yellow in color than their brown relatives and were unable to perform photosynthesis. They found, unexpectedly, that in coral, these mutant algae were still able to live and grow because the coral gives the algae sustenance to grow.
As luck would have it, by using next-generation DNA sequencing and a lot of data analysis, the researchers were also able to use the mutants to discover the gene responsible for chlorophyll c production. “Discovering the chlorophyll c gene was not the initial goal of our work. We made the mutants for another reason, but I guess we were just lucky,” Xiang said.
With new insight into the genetic basis for producing chlorophyll c, the researchers are hopeful that the work could eventually help stem the tide of coral bleaching seen worldwide. Furthermore, there are land-based applications that could help people adapt to climate change.
“The identification of the biosynthetic pathway for chlorophyll c is more than a scientific curiosity; it’s a potential game-changer for sustainable energy and food security,” said Robert Jinkerson, UCR chemical engineering professor and study co-author.
“By unlocking the secrets of this key pigment, we’re not only gaining insights into the lifeblood of marine ecosystems but also pioneering a path towards developing more robust crops and efficient biofuels,” Jinkerson said.
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