GN/ New viruses that could cause epidemics on the horizon
Genetics biweekly vol.57, 10th May — 24th May
TL;DR
- Suddenly they appear and — like the SARS-CoV-2 coronavirus — can trigger major epidemics: Viruses that nobody had on their radar. They are not new, but they have changed genetically. In particular, the exchange of genetic material between different virus species can lead to the sudden emergence of threatening pathogens with significantly altered characteristics. This is suggested by current genetic analyses carried out by an international team of researchers.
- Introns are one of our genome’s biggest mysteries. They are DNA sequences that interrupt the sensible protein-coding information in your genes, and need to be ‘spliced out.’ In a new paper, researchers reports on a surprising discovery about the spliceosome that could tell us more about the evolution of different species and the way cells have adapted to the strange problem of introns.
- Researchers have made a surprising discovery in the structure of the centromere, a structure that is involved in ensuring that chromosomes are segregated properly when a cell divides. Mistakes in chromosome segregation can lead to cell death and cancer development. The researchers discovered that the centromere consists of two subdomains. This fundamental finding has important implications for the process of chromosome segregation and provides new mechanisms underlying erroneous divisions in cancer cells.
- A research team has unveiled a breakthrough in understanding how specific genetic sequences, known as pseudogenes, evolve.
- Elucidating the relationship between the sequences of non-coding regulatory elements and their target genes is key to understanding gene regulation and its variation between plant species and ecotypes. Now, an international research team developed deep learning models that link gene sequence data with mRNA copy numbers for several plant species and predict the regulatory effect of gene sequence variation.
- The earliest stages of mammalian embryo development are like an orchestra performance, where everyone must play at the exact right moment and in perfect harmony. New research identifies one of the conductors making sense of the chaos.
- Researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodeling works in human cells and the future development of new drugs.
- A recent study led to the development of a powerful epigenetic editing technology. The system unlocks the ability to precisely program chromatin modifications at any specific position in the genome, to understand their causal role in transcription regulation. This innovative approach will help to investigate the role of chromatin modifications in many biological processes and to program desired gene activity responses, which may prove useful in disease settings.
- Plants’ ability to sense light and temperature, and their ability to adapt to climate change, hinges on free-forming structures in their cells whose function was, until now, a mystery. Researchers have now determined how these structures work on a molecular level, as well as where and how they form.
- Researchers have found that herpesvirus infection modifies the structure and normal function of the mitochondria in the host cell. The new information will help to understand the interaction between herpesvirus and host cells. Knowledge can be utilized in the development of viral treatments.
- 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
According to Global Genetic Engineering Market Research Report: The genetic engineering market is projected to grow from USD 1.36 Billion in 2023 to USD 7.73 Billion by 2032, exhibiting a compound annual growth rate (CAGR) of 24.20% during the forecast period (2023–2032).
Growing demand for synthetic genes and increased use of CRISPR genome editing technology across various biotechnology industries are the key market drivers enhancing the market growth. In addition, it’s projected that increased government financing, a rise in the output of genetically modified crops, and an increase in genomics studies will all contribute to the expansion.
Latest Research
Deep mining of the Sequence Read Archive reveals major genetic innovations in coronaviruses and other nidoviruses of aquatic vertebrates
by Chris Lauber, Xiaoyu Zhang, Josef Vaas, Franziska Klingler, Pascal Mutz, Arseny Dubin, Thomas Pietschmann, Olivia Roth, Benjamin W. Neuman, Alexander E. Gorbalenya, Ralf Bartenschlager, Stefan Seitz in PLOS Pathogens
Suddenly they appear and — like the SARS-CoV-2 coronavirus — can trigger major epidemics: Viruses that nobody had on their radar. They are not really new, but they have changed genetically. In particular, the exchange of genetic material between different virus species can lead to the sudden emergence of threatening pathogens with significantly altered characteristics. This is suggested by current genetic analyses carried out by an international team of researchers. Virologists from the German Cancer Research Center (DKFZ) were in charge of the large-scale study.
“Using a new computer-assisted analysis method, we discovered 40 previously unknown nidoviruses in various vertebrates from fish to rodents, including 13 coronaviruses,” reports DKFZ group leader Stefan Seitz. With the help of high-performance computers, the research team, which also includes Chris Lauber’s working group from the Helmholtz Center for Infection Research in Hanover, has sifted through almost 300,000 data sets. According to virologist Seitz, the fact that we can now analyze such huge amounts of data in one go opens up completely new perspectives.
Virus research is still in its relative infancy. Only a fraction of all viruses occurring in nature are known, especially those that cause diseases in humans, domestic animals and crops. The new method therefore promises a quantum leap in knowledge with regard to the natural virus reservoir. Stefan Seitz and his colleagues sent genetic data from vertebrates stored in scientific databases through their high-performance computers with new questions. They searched for virus-infected animals in order to obtain and study viral genetic material on a large scale. The main focus was on so-called nidoviruses, which include the coronavirus family.
Nidoviruses, whose genetic material consists of RNA (ribonucleic acid), are widespread in vertebrates. This species-rich group of viruses has some common characteristics that distinguish them from all other RNA viruses and document their relationship. Otherwise, however, nidoviruses are very different from each other, i.e. in terms of the size of their genome.
One discovery is particularly interesting with regard to the emergence of new viruses: In host animals that are simultaneously infected with different viruses, a recombination of viral genes can occur during virus replication. “Apparently, the nidoviruses we discovered in fish frequently exchange genetic material between different virus species, even across family boundaries,” says Stefan Seitz. And when distant relatives “crossbreed,” this can lead to the emergence of viruses with completely new properties. According to Seitz, such evolutionary leaps can affect the aggressiveness and dangerousness of the viruses, but also their attachment to certain host animals.
“A genetic exchange, as we have found in fish viruses, will probably also occur in mammalian viruses,” explains Stefan Seitz. Bats, which — like shrews — are often infected with a large number of different viruses, are considered a true melting pot. The SARS-CoV-2 coronavirus probably also developed in bats and jumped from there to humans.
After gene exchange between nidoviruses, the spike protein with which the viruses dock onto their host cells often changes. Chris Lauber, first author of the study, was able to show this by means of family tree analyses. Modifying this anchor molecule can significantly change the properties of the viruses to their advantage — by increasing their infectiousness or enabling them to switch hosts. A change of host, especially from animals to humans, can greatly facilitate the spread of the virus, as the corona pandemic has emphatically demonstrated. Viral “game changers” can suddenly appear at any time, becoming a massive threat and — if push comes to shove — triggering a pandemic. The starting point can be a single double-infected host animal.
The new high-performance computer process could help to prevent the spread of new viruses. It enables a systematic search for virus variants that are potentially dangerous for humans, explains Stefan Seitz. And the DKFZ researcher sees another important possible application with regard to his special field of research, virus-associated carcinogenesis:
“I could imagine that we could use the new High Performance Computing (HPC) to systematically examine cancer patients or immunocompromised people for viruses. We know that cancer can be triggered by viruses, the best-known example being human papillomaviruses. But we are probably only seeing the tip of the iceberg so far. The HPC method offers the opportunity to track down viruses that, previously undetected, nestle in the human organism and increase the risk of malignant tumors.”
Intron lariat spliceosomes convert lariats to true circles: implications for intron transposition
by Manuel Ares, Haller Igel, Sol Katzman, John P. Donohue in Genes & Development
Although you may not appreciate them, or have even heard of them, throughout your body, countless microscopic machines called spliceosomes are hard at work. As you sit and read, they are faithfully and rapidly putting back together the broken information in your genes by removing sequences called “introns” so that your messenger RNAs can make the correct proteins needed by your cells.
Introns are perhaps one of our genome’s biggest mysteries. They are DNA sequences that interrupt the sensible protein-coding information in your genes, and need to be “spliced out.” The human genome has hundreds of thousands of introns, about 7 or 8 per gene, and each is removed by a specialized RNA protein complex called the “spliceosome” that cuts out all the introns and splices together the remaining coding sequences, called exons. How this system of broken genes and the spliceosome evolved in our genomes is not known. Over his long career, Manny Ares, UC Santa Cruz distinguished professor of molecular, cellular, and developmental biology, has made it his mission to learn as much about RNA splicing as he can.
“I’m all about the spliceosome,” Ares said. “I just want to know everything the spliceosome does — even if I don’t know why it is doing it.”
In a new paper, Ares reports on a surprising discovery about the spliceosome that could tell us more about the evolution of different species and the way cells have adapted to the strange problem of introns. The authors show that after the spliceosome is finished splicing the mRNA, it remains active and can engage in further reactions with the removed introns.
This discovery provides the strongest indication we have so far that spliceosomes could be able to reinsert an intron back into the genome in another location. This is an ability that spliceosomes were not previously believed to possess, but which is a common characteristic of “Group II introns,” distant cousins of the spliceosome that exist primarily in bacteria.
The spliceosome and Group II introns are believed to share a common ancestor that was responsible for spreading introns throughout the genome, but while Group II introns can splice themselves out of RNA and then directly back into DNA, the “spliceosomal introns” that are found in most higher-level organisms require the spliceosome for splicing and were not believed to be reinserted back into DNA. However, Ares’s lab’s finding indicates that the spliceosome might still be reinserting introns into the genome today. This is an intriguing possibility to consider because introns that are reintroduced into DNA add complexity to the genome, and understanding more about where these introns come from could help us to better understand how organisms continue to evolve.
An organism’s genes are made of DNA, in which four bases, adenine (A), cytosine (C), guanine (G) and thymine (T) are ordered in sequences that code for biological instructions, like how to make specific proteins the body needs. Before these instructions can be read, the DNA gets copied into RNA by a process known as transcription, and then the introns in that RNA have to be removed before a ribosome can translate it into actual proteins.
The spliceosome removes introns using a two-step process that results in the intron RNA having one of its ends joined to its middle, forming a circle with a tail that looks like a cowboy’s “lariat,” or lasso. This appearance has led to them being named “lariat introns.” Recently, researchers at Brown University who were studying the locations of the joining sites in these lariats made an odd observation — some introns were actually circular instead of lariat shaped. This observation immediately got Ares’s attention. Something seemed to be interacting with the lariat introns after they were removed from the RNA sequence to change their shape, and the spliceosome was his main suspect.
“I thought that was interesting because of this old, old idea about where introns came from,” Ares said. “There is a lot of evidence that the RNA parts of the spliceosome, the snRNAs, are closely related to Group II introns.”
Because the chemical mechanism for splicing is very similar between the spliceosomes and their distant cousins, the Group II introns, many researchers have theorized that when the process of self-splicing became too inefficient for Group II introns to reliably complete on their own, parts of these introns evolved to become the spliceosome. While Group II introns were able to insert themselves directly back into DNA, however, spliceosomal introns that required the help of spliceosomes were not thought to be inserted back into DNA.
“One of the questions that was sort of missing from this story in my mind was, is it possible that the modern spliceosome is still able to take a lariat intron and insert it somewhere in the genome?” Ares said. “Is it still capable of doing what the ancestor complex did?”
To begin to answer this question, Ares decided to investigate whether it was indeed the spliceosome that was making changes to the lariat introns to remove their tails. His lab slowed the splicing process in yeast cells, and discovered that after the spliceosome released the mRNA that it had finished splicing introns from, it hung onto intron lariats and reshaped them into true circles. The Ares lab was able to reanalyze published RNA sequencing data from human cells and found that human spliceosomes also had this ability.
“We are excited about this because while we don’t know what this circular RNA might do, the fact that the spliceosome is still active suggests it may be able to catalyze the insertion of the lariat intron back into the genome,” Ares said.
If the spliceosome is able to reinsert the intron into DNA, this would also add significant weight to the theory that spliceosomes and Group II introns shared a common ancestor long ago.
Now that Ares and his lab have shown that the spliceosome has the catalytic ability to hypothetically place introns back into DNA like their ancestors did, the next step is for the researchers to create an artificial situation in which they “feed” a DNA strand to a spliceosome that is still attached to a lariat intron and see if they can actually get it to insert the intron somewhere, which would present “proof of concept” for this theory.
If the spliceosome is able to reinsert introns into the genome, it is likely to be a very infrequent event in humans, because the human spliceosomes are in incredibly high demand and therefore do not have much time to spend with removed introns. In other organisms where the spliceosome isn’t as busy, however, the reinsertion of introns may be more frequent. Ares is working closely with UCSC Biomolecular Engineering Professor Russ Corbett-Detig, who has recently led a systematic and exhaustive hunt for new introns in the available genomes of all intron-containing species.
The paper showed that intron “burst” events far back in evolutionary history likely introduced thousands of introns into a genome all at once. Ares and Corbett-Detig are now working to recreate a burst event artificially, which would give them insight into how genomes reacted when this happened. Ares said that his cross-disciplinary partnership with Corbett-Detig has opened the doors for them to really dig into some of the biggest mysteries about introns that would probably be impossible for them to understand fully without their combined expertise.
“It is the best way to do things,” Ares said. “When you find someone who has the same kind of questions in mind but a different set of methods, perspectives, biases, and weird ideas, that gets more exciting. That makes you feel like you can break out and solve a problem like this, which is very complex.”
Vertebrate centromeres in mitosis are functionally bipartite structures stabilized by cohesin
by Carlos Sacristan, Kumiko Samejima, Lorena Andrade Ruiz, Moonmoon Deb, et al in Cell
Researchers from the Kops group in collaboration with researchers from the University of Edinburgh, made a surprising new discovery in the structure of the centromere, a structure that is involved in ensuring that chromosomes are segregated properly when a cell divides. Mistakes in chromosome segregation can lead to cell death and cancer development. The researchers discovered that the centromere consists of two subdomains. This fundamental finding has important implications for the process of chromosome segregation and provides new mechanisms underlying erroneous divisions in cancer cells.
Our bodies consist of trillions of cells, most of which have a limited life span and therefore need to reproduce to replace the old ones. This reproduction process is referred to as cell division or mitosis. During mitosis, the parent cell will duplicate its chromosomes in order to pass down the genetic material to the daughter cells. The resulting identical pairs of chromosomes, the sister chromatids, are held together by a structure called the centromere. The sister chromatids then need to be evenly split over the two daughter cells to ensure that each daughter cell is an exact copy of the parent cell. If errors happen during the segregation, one daughter cell will have too many chromosomes, while the other has too few. This can lead to cell death or cancer development.
The centromere is a part of the chromosome that plays a vital role in chromosome segregation during mitosis. The process of dividing the sister chromatids over the cells is guided by the interaction between the centromeres and structures known as spindle microtubules. These spindle microtubules are responsible for pulling the chromatids apart and thus separating the two sister chromatids. Carlos Sacristan Lopez, the first author of this study, explains: ‘If the attachment of the centromere to the spindle microtubules does not occur properly it leads to chromosome segregation mistakes which are frequently observed in cancer.’ Understanding the structure of the centromere can contribute to more insights into the function of the centromere and its role in erroneous chromosomal segregation.
To investigate the centromere structure, the researchers used a combination of imaging and sequencing techniques. The super-resolution microscopy imaging took place at the Hubrecht Institute, while the group of Bill Earnshaw performed the sequencing. This collaboration led to a surprising new discovery in the centromere structure. Previously believed to consist of a compact structure attaching to multiple spindle microtubules, it was instead revealed that the centromere consists of two subdomains.
Carlos explains: ‘This discovery was very surprising, as subdomains bind microtubules independently of each other. Yet, to form correct attachments, they must remain closely connected. In cancer cells, however, we often observe that subdomains uncouple, resulting in erroneous attachments and chromosome segregation errors.’
This very exciting and fundamental discovery contributes to our understanding of the origin of chromosome segregation errors which are frequently seen in cancer.
The physical and evolutionary energy landscapes of devolved protein sequences corresponding to pseudogenes
by Hana Jaafari, Carlos Bueno, Nicholas P. Schafer, Jonathan Martin, Faruck Morcos, Peter G. Wolynes in Proceedings of the National Academy of Sciences
Rice University’s Peter Wolynes and his research team have unveiled a breakthrough in understanding how specific genetic sequences, known as pseudogenes, evolve.
Led by Wolynes, the D.R. Bullard-Welch Foundation Professor of Science, professor of chemistry, biosciences and physics and astronomy and co-director of the Center for Theoretical Biological Physics (CTBP), the team focused on deciphering the complex energy landscapes of de-evolved, putative protein sequences corresponding to pseudogenes.
Pseudogenes are segments of DNA that once encoded proteins but have since lost their ability to do so due to sequence degradation — a phenomenon referred to as devolution. Here, devolution represents an unconstrained evolutionary process that occurs without the usual evolutionary pressures that regulate functional protein-coding sequences. Despite their inactive state, pseudogenes offer a window into the evolutionary journey of proteins.
“Our paper explains that proteins can de-evolve,” Wolynes said. “A DNA sequence can, by mutations or other means, lose the signal that tells it to code for a protein. The DNA continues to mutate but does not have to lead to a sequence that can fold.”
The researchers studied junk DNA in a genome that has de-evolved. Their research revealed that a mutation accumulation in pseudogene sequences typically disrupts the native network of stabilizing interactions, making it challenging for these sequences, if they were to be translated, to fold into functional proteins. However, the researchers observed instances where certain mutations unexpectedly stabilized the folding of pseudogenes at the cost of altering their previous biological functions.
They identified specific pseudogenes, such as cyclophilin A, profilin-1 and small ubiquitin-like modifier 2 protein, where stabilizing mutations occurred in regions crucial for binding to other molecules and other functions, suggesting a complex balance between protein stability and biological activity. Moreover, the study highlights the dynamic nature of protein evolution as some previously pseudogenized genes may regain their protein-coding function over time despite undergoing multiple mutations.
Using sophisticated computational models, the researchers interpreted the interplay between physical folding landscapes and the evolutionary landscapes of pseudogenes. Their findings provide evidence that the funnellike character of folding landscapes comes from evolution.
“Proteins can de-evolve and have their ability to fold compromised over time due to mutations or other means,” Wolynes said. “Our study offers the first direct evidence that evolution is shaping the folding of proteins.”
Along with Wolynes, the research team includes lead author and applied physics graduate student Hana Jaafari ; CTBP postdoctoral associate Carlos Bueno ; University of Texas at Dallas graduate student Jonathan Martin; Faruck Morcos, associate professor in the Department of Biological Sciences at UT-Dallas; and CTBP biophysics researcher Nicholas P. Schafer. The implications of this research extend beyond theoretical biology with potential applications in protein engineering, Jaafari said.
“It would be interesting to see if someone at a lab could confirm our results to see what happens to the pseudogenes that were more physically stable,” Jaafari said. “We have an idea based on our analysis, but it’d be compelling to get some experimental validation.”
Deep learning the cis-regulatory code for gene expression in selected model plants
by Fritz Forbang Peleke, Simon Maria Zumkeller, Mehmet Gültas, Armin Schmitt, Jędrzej Szymański in Nature Communications
Elucidating the relationship between the sequences of non-coding regulatory elements and their target genes is key to understanding gene regulation and its variation between plant species and ecotypes. Now, an international research team led by IPK Leibniz Institute and with the participation of Forschungszentrum Jülich developed deep learning models that link gene sequence data with mRNA copy number for several plant species and predicted the regulatory effect of gene sequence variation.
Genome sequencing technology provides thousands of new plant genomes annually. In agriculture, researchers merge this genomic information with observational data (measuring various plant traits) to identify correlations between genetic variants and crop traits like seed count, resistance to fungal infections, fruit color, or flavor. However, the grasp of how genetic variation influences gene activity at the molecular level is quite limited. This gap in knowledge hinders the breeding of “smart crops” with enhanced quality and reduced negative environmental impact achieved by combination of specific gene variants of known function.
Researchers from the IPK Leibniz Institute and Forschungszentrum Jülich (FZ) have made a significant breakthrough to tackle this challenge. Led by Dr. Jedrzej Jakub Szymanski, the international research team trained interpretable deep learning models, a subset of AI algorithms, on a vast dataset of genomic information from various plant species. “These models not only were able to accurately predict gene activity from sequences but also pinpoint which sequence parts contribute to these predictions,” explains the head of IPK’s research group “Network Analysis and Modelling.” The AI technology which the researchers applied is akin to that used in computer vision, which involves recognizing facial features in images and inferring emotions.
In contrast to previous approaches based on statistical enrichment, here the researchers combined identification of sequence features with determination of the mRNA copy number in the frame of a mathematical model that has been trained accounting for biological information on gene model structure and sequence homology, thus gene evolution.
“We were truly amazed by the effectiveness. Within a few days of training, we rediscovered many known regulatory sequences and found that about 50% of the features identified were entirely new. These models excellently generalized across plant species they were not trained on, making them valuable for analyzing newly sequenced genomes,” says Dr. Jedrzej Jakub Szymanski. “And we specifically demonstrated their application in diverse tomato cultivars with long-read sequencing data. We pinpointed specific regulatory sequence variations that explained observed differences in gene activity and, consequently, variations in shape, color, and robustness. This is a remarkable improvement over classically used statistical associations of single nucleotide polymorphisms.”
The team has openly shared their models and provided a web interface for their use. “Interestingly, much effort went into degrading our model’s performance. To avoid overly optimistic results due to AI finding shortcuts required from me a deep dive into gene regulation biology to eliminate any potential bias, reduce data leakage and overfitting,” says Fritz Forbang Peleke, the lead machine learning researcher and first author of the study.
Dr. Simon Zumkeller, a co-author and evolutionary biologist from FZ Jülich, remarked, “With the presented analyses we can investigate and compare gene regulation in plants and infer its evolution. For practical applications, the method provides a new foundation, too. We are approaching the routine identification of gene regulatory elements in known and newly sequenced plant genomes, in various tissues, and under different environmental conditions.”
The Wnt-dependent master regulator NKX1–2 controls mouse pre-implantation development
by Shoma Nakagawa, Davide Carnevali, Xiangtian Tan, Mariano J. Alvarez, David-Emlyn Parfitt, Umberto Di Vicino, Karthik Arumugam, William Shin, Sergi Aranda, Davide Normanno, Ruben Sebastian-Perez, Chiara Cannatá, Paola Cortes, Maria Victoria Neguembor, Michael M. Shen, Andrea Califano, Maria Pia Cosma in Stem Cell Reports
Early embryonic development is tumultuous. It involves a rapid sequence of events, including cell division, differentiation, and lots of compartments moving around within each cell. Like an orchestra performance where each member of the band must start playing at the exact right moment and in perfect harmony, these processes need to be precisely timed and coordinated to ensure the embryo develops normally.
How cells make sense of this chaos at the very beginning of an embryo’s development is an open question. The protein NKX1–2 a crucial role, according to a new study published by ICREA Research Professor Pia Cosma at the Centre for Genomic Regulation (CRG) in Barcelona and Professor Andrea Califano President of the Chan Zuckerberg Biohub New York and Professor at Columbia University.
NKX1–2 behaves like an orchestra’s conductor, skilfully ensuring that the genetic instructions for developing the embryo are executed correctly and at the right times. The protein helps manage the production and organisation of the cell’s machinery for making proteins (like ribosomes) and is also crucial for keeping chromosomes organized and properly distributed when cells divide.
When the researchers experimentally inhibited the function of NKX1–2 in mice, they found the nucleolus (a part of the nucleus that assembles ribosomes) was severely altered, disrupting the embryo’s ability to produce ribosomes correctly. They also found the 2- to 4-cell embryos could not distribute chromosomes correctly during cell division, and would stop growing at these very early stages of development.
“NKX1–2 belongs to a protein family which is known to play crucial roles in early development and organ formation. While we knew that members of this family were important in general development, NKX1–2’s specific role, especially in early embryonic stages, wasn’t well understood,” explains ICREA Research Professor Pia Cosma, corresponding author of the study.
“It is intriguing that such mechanistic determinants of embryogenesis could be identified by assembling and interrogating a mouse embryonic stem cell regulatory network, using methodologies originally developed for cancer research,” adds Dr. Califano, co-corresponding author on the study.
Given the similarities in early developmental processes between mice and humans, the findings offer new clues into unexplained causes of developmental problems, including miscarriages. Miscarriages often result from chromosomal abnormalities, which can arise from issues like those observed in the study — improper chromosome segregation and cell division errors. Further research could explore if there is a human counterpart that influences these fundamental processes as it does in mice, and what happens when it fails.
Despite the importance of NKX1–2 in early embryo development, the researchers suspect more ‘conductors’ remain to be discovered. “NKX1–2 is expressed at very low levels, which makes it extremely difficult to detect. It’s like trying to find a needle in a haystack using traditional methods in biology. Repeating our methods could help find other rare and critical elements that have been historically overlooked,” adds Dr. Cosma.
A chemical inhibitor of IST1-CHMP1B interaction impairs endosomal recycling and induces noncanonical LC3 lipidation
by Anastasia Knyazeva, Shuang Li, Dale P. Corkery, Kasturika Shankar, Laura K. Herzog, Xuepei Zhang, Birendra Singh, Georg Niggemeyer, David Grill, Jonathan D. Gilthorpe, Massimiliano Gaetani, Lars-Anders Carlson, Herbert Waldmann, Yao-Wen Wu in Proceedings of the National Academy of Sciences
In a study, Umeå researchers describe a natural product-like molecule, Tantalosin, that inhibits interaction between two proteins in complexes that reshape membranes inside the cell. The findings lead to a deeper understanding of how membrane remodelling works in human cells and future development of new drugs.
“Our study is a good case to use small molecules as valuable chemical tools for understanding complex biological mechanisms. I am happy to coordinate a fantastic collaboration with colleagues in Umeå, Stockholm and Germany,” says Yaowen Wu, professor at the Department of Chemistry at Umeå University.
Membranes of cells are made of lipids and proteins, and they serve barrier functions for cells and intracellular organelles. Membranes of cells are highly dynamic mosaic-fluid structures that undergo constant reshaping. The endosomal sorting complex required for transport (ESCRT) is tasked with remodelling membranes inside the cell. The ESCRT machinery assembles at the site in the cell where membranes need deformation and then forms helical protein polymers that can contract and pinch off cell membranes.
Previously, Professor Yaowen Wu and his group, in collaboration with Professor Herbert Waldmann’s laboratory at Max Planck Institute Dortmund in Germany, identified a chemical molecule, Tantalosin, that induces a phenotype like autophagy — a self-eating process in the cell. Tantalosin is a synthetic molecule inspired by alkaloids from the medical plant Cinchona. They observed a very interesting phenomenon in the cell treated with Tantalosin and investigated further the molecular mechanism how Tantalosin works in the cell.
In collaboration with the chemical proteomics core facility at SciLifeLab in Karolinska Institute the team scrutinized potential cellular targets of Tantalosin.
“To our surprise, we found that none of the autophagy-related proteins were on the list of potential targets. However, IST1 protein in ESCRT complexes was identified and validated as the cellular target of Tantalosin. We were excited to work on deciphering this unexpected connection between ESCRT complexes and autophagy,” says first author Anastasia Knyazeva, who just recently completed her doctoral degree at the Department of Chemistry at Umeå University.
The researchers characterized the mechanism using a range of biochemical and cell biological methods. When they studied protein-protein interaction in solution, they found that Tantalosin completely stops the interaction between IST1 and its binding partner CHMP1B.
“We then took a closer look at these two proteins using a transmission electron microscope in collaboration with Kasturika Shankar, a PhD student from Lars-Anders Carlson’s lab at Umeå University. Intriguingly, Tantalosin disrupts the formation of ordered IST1-CHMP1B filaments,” explains Shuang Li, the paper’s co-first author and postdoctoral fellow at the Department of Chemistry at Umeå University.
Furthermore, the researchers looked inside the cell and found that Tantalosin rapidly disrupts the recycling of cell-surface receptors back to the cell surface. This property could be potentially beneficial for treating certain types of cancers that are driven by cell-surface receptors.
In this study, the researchers found that LC3 protein, which is usually a hallmark of autophagy, is linked to the endosomal membranes during Tantalosin treatment. Interestingly, the canonical autophagic degradation was not observed. Instead, they found that the process follows a noncanonical autophagy pathway.
“We believe that Tantalosin can be a unique molecule that facilitates understanding new functions of noncanonical conjugation of LC3 to endosomal membranes. We hope that further studies will reveal the role of LC3-membrane conjugation and its associated proteins in membrane deformation processes,” says Anastasia Knyazeva.
Systematic epigenome editing captures the context-dependent instructive function of chromatin modifications
by Cristina Policarpi, Marzia Munafò, Stylianos Tsagkris, Valentina Carlini, Jamie A. Hackett in Nature Genetics
Understanding how genes are regulated at the molecular level is a central challenge in modern biology. This complex mechanism is mainly driven by the interaction between proteins called transcription factors, DNA regulatory regions, and epigenetic modifications — chemical alterations that change chromatin structure. The set of epigenetic modifications of a cell’s genome is referred to as the epigenome.
In a study, scientists from the Hackett Group at EMBL Rome have developed a modular epigenome editing platform — a system to program epigenetic modifications at any location in the genome. The system allows scientists to study the impact of each chromatin modification on transcription, the mechanism by which genes are copied into mRNA to drive protein synthesis.
Chromatin modifications are thought to contribute to the regulation of key biological processes such as development, response to environmental signals, and disease. To understand the effects of specific chromatin marks on gene regulation, previous studies have mapped their distribution in the genomes of healthy and diseased cell types. By combining this data with gene expression analysis and the known effects of perturbing specific genes, scientists have ascribed functions to such chromatin marks.
However, the causal relationship between chromatin marks and gene regulation has proved difficult to determine. The challenge lies in dissecting the individual contributions of the many complex factors involved in such regulation — chromatin marks, transcription factors, and regulatory DNA sequences.
Scientists from the Hackett Group developed a modular epigenome editing system to precisely program nine biologically important chromatin marks at any desired region in the genome. The system is based on CRISPR — a widely used genome editing technology that allows researchers to make alterations in specific DNA locations with high precision and accuracy.
Such precise perturbations enabled them to carefully dissect cause-and-consequence relationships between chromatin marks and their biological effects. The scientists also designed and employed a ‘reporter system’, which allowed them to measure changes in gene expression at single-cell level and to understand how changes in the DNA sequence influence the impact of each chromatin mark. Their results reveal the causal roles of a range of important chromatin marks in gene regulation. For example, the researchers found a new role for H3K4me3, a chromatin mark that was previously believed to be a result of transcription. They observed that H3K4me3 can actually increase transcription by itself if artificially added to specific DNA locations.
“This was an extremely exciting and unexpected result that went against all our expectations,” said Cristina Policarpi, postdoc in the Hackett Group and leading scientist of the study. “Our data point towards a complex regulatory network, in which multiple governing factors interact to modulate the levels of gene expression in a given cell. These factors include the pre-existing structure of the chromatin, the underlying DNA sequence, and the location in the genome.”
Hackett and colleagues are currently exploring avenues to leverage this technology through a promising start-up venture. The next step will be to confirm and expand these conclusions by targeting genes across different cell types and at scale. How chromatin marks influence transcription across the diversity of genes and downstream mechanisms, also remains to be clarified.
“Our modular epigenetic editing toolkit constitutes a new experimental approach to dissect the reciprocal relationships between the genome and epigenome,” said Jamie Hackett, Group Leader at EMBL Rome. “The system could be used in the future to more precisely understand the importance of epigenomic changes in influencing gene activity during development and in human disease. On the other hand, the technology also unlocks the ability to program desired gene expression levels in a highly tunable manner. This is an exciting avenue for precision health applications and may prove useful in disease settings.”
Distinguishing individual photobodies using Oligopaints reveals thermo-sensitive and -insensitive phytochrome B condensation at distinct subnuclear locations
by Juan Du, Keunhwa Kim, Meng Chen in Nature Communications
Plants’ ability to sense light and temperature, and their ability to adapt to climate change, hinges on free-forming structures in their cells whose function was, until now, a mystery.
For the first time, UC Riverside researchers have determined how these structures work on a molecular level, as well as where and how they form. Scientists have long studied membrane-bound compartments, called organelles, in plant cells, such as the Golgi apparatus, mitochondria, and most significantly, the nucleus, where DNA gets copied and transcribed into RNA. However, much less is known about the membrane-free organelles that can dynamically assemble and disassemble inside the nucleus, such as the photobodies that help to sense light and temperature in plants.
“At one time, people called these photobodies ‘garbage cans,’ because they didn’t understand them. When people don’t understand something, they call it useless. But they aren’t useless at all,” said UCR botany professor Meng Chen, senior author of both papers. “They are a new frontier in science.”
Part of the challenge in studying photobodies, or membrane-less organelles in general, is that molecules are moving in and out of them constantly. This makes it difficult to distinguish the function of the components inside the organelles versus those outside. Additionally, these photobodies only form in the light. Chen spent two decades working on this problem before his lab found a method that helped unlock the mystery of the organelles’ function.
In the past, he would remove a gene in a laboratory plant and try to observe any changes in the photobodies and the plants’ light or temperature responses. This approach yielded partial success. His laboratory identified a gene that made it impossible for the membrane-less organelles to assemble. Knocking out this gene made the plants partially blind to light. “We saw that these organelles are involved in light sensing, but we realized this was a correlation, not causation,” Chen said. To learn more, the researchers tried enhancing the size of the organelles, rather than eliminating them. This strategy, detailed in one of the new papers, proved successful. With bigger organelles, it was possible to see the function.
“What we saw, ultimately, is that the membrane-less organelles help plants distinguish a whole range of different light intensities. Without them, plants would not be able to ‘see’ changes in light intensity,” Chen said.
In a related set of experiments, described in the second Nature Communications paper, the researchers tested the relationship between these organelles and temperature. Previously, the group had shown that if temperature increases, the number of these organelles decreases. The group theorized that temperature-sensitivity would be a function of where in the cell the organelles formed. Other researchers proposed that the formation of the organelles is random, but Chen suspected this was not the case.
“There is not much in nature that is completely random,” Chen said. “At the airport, do people get together in the middle of nowhere, or are they usually in the waiting areas and at airline counters? Anything that has an important function is not usually random.”
The formation of photobodies, it turns out, is not random, either. More than half of them are near centromeres, the region of a chromosome harboring silenced genes. At 16 degrees, there were nine types of membrane-less organelles in the cells. At 27 degrees, the number dropped to only five types. Though all of them contain the temperature-sensing protein phytochrome B, some of these organelles are sensitive to temperature, and others aren’t.
Going forward, the researchers are hoping to show that it is possible to change the plants’ sensitivity to light and temperature by manipulating where the organelles form. This is particularly important if people want to continue growing food crops in a hotter, brighter world. California grows half of the country’s fruits and vegetables. But scientists estimate that without mitigation of greenhouse gas emissions, the average temperatures in the state could increase by 11 degrees by the end of the century, which would seriously impact crop growth.
“To predict and mitigate climate change, we need to understand how plants sense and respond to their environment, especially temperature,” Chen said. “Temperature is not related only to growth and size. It’s related to everything: flowering time, fruit development, pathogen response, and immunity.”
Progression of herpesvirus infection remodels mitochondrial organization and metabolism
by Simon Leclerc, Alka Gupta, Visa Ruokolainen, Jian-Hua Chen, Kari Kunnas, Axel A. Ekman, Henri Niskanen, Ilya Belevich, Helena Vihinen, Paula Turkki, Ana J. Perez-Berna, Sergey Kapishnikov, Elina Mäntylä, Maria Harkiolaki, Eric Dufour, Vesa Hytönen, Eva Pereiro, Tony McEnroe, Kenneth Fahy, Minna U. Kaikkonen, Eija Jokitalo, Carolyn A. Larabell, Venera Weinhardt, Salla Mattola, Vesa Aho, Maija Vihinen-Ranta in PLOS Pathogens
Researchers at the University of Jyväskylä have found that herpesvirus infection modifies the structure and normal function of the mitochondria in the host cell. The new information will help to understand the interaction between herpesvirus and host cells. Knowledge can be utilized in the development of viral treatments.
Herpesviruses not only cause significant diseases but are also promising candidates for oncolytic therapy. The HSV-1 infection depends on the nuclear DNA replication, transcription machinery, and mitochondrial metabolism of the host cell. In the Department of Biological and Environmental Science of the University of Jyväskylä, docent Maija Vihinen-Ranta, with her research team, investigated time-dependent mitochondrial changes as HSV-1 infection proceeds from early to late infection.
Recent research shows that the infection leads to significant transcriptional modification of genes encoding proteins involved in the mitochondrial network, such as the respiratory chain, apoptosis, and the structural organization of mitochondria. Findings indicate that the infection leads to significant alterations in mitochondrial structure and function, including changes in mitochondrial morphology and distribution, thickening and shortening of cristae, an increase in the number and area of contact sites between mitochondria and the endoplasmic reticulum, as well as a rise in mitochondrial calcium ion content and proton leak.
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