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29 November 2024

An international consortium of researchers from the University of Michigan, the Université de Strasbourg, and the Technische Universität Berlin uncover important players in the mechanistics and the machinery involved in the bacterial ribosome-mRNA translation initiation process through an intercollegiate collaborative new study. 

Adrien Chauvier, Ph.D., is a Senior Scientist in the Nils Walter Lab at the University of Michigan, and one of four lead co-authors on a new paper published today in Science. The article, “Molecular basis of mRNA delivery to the bacterial ribosome,” details remarkable findings from a study that sought to visualize the early stages of ribosome recruitment to the nascent messenger RNA (mRNA) as it is transcribed by RNA polymerase (RNAP) and close the gap on a poorly understood aspect of the coupling of these two sequential steps needed to first transcribe mRNA from the genome, then translate it into proteins in the bacterial cell.

Weixlbaumer and Webster enlisted the expertise of Chauvier and Center for RNA Biomedicine Co-Director Nils Walter, Ph.D., from the University of Michigan in the USA; Juri Rappsilber, Ph.D., from Technische Universität Berlin; and a coalition of scientists from France, the US, Germany, and the United Kingdom. 

Walter and Chauvier previously investigated how structural RNAs in bacteria modulate protein production through transcription-translation coupling. Their results were published in The Proceedings of the National Academy of Sciences (PNAS) in 2021.

“Albert was very interested in our work, and wrote a commentary on our paper,” Chauvier said. “It was humbling. I had followed his work for years and was thrilled when he later reached out. His lab analyzes the structure of the ribosome-RNAP complex ‘flash-frozen’ in time, and we look at the dynamic kinetics of that complex ‘in motion.’ It’s exciting how things like this come together. It’s what I love about science.”

The researchers employed various technologies and methodologies per each lab’s specialty — cryo-EM in Weixlbaumer’s group, and the Berlin group’s in-cell crosslinking mass spectrometry carried out by Andrea Graziadei — to examine the processes involved. 

With expertise in biophysics, Chauvier and Walter utilized their advanced single molecule fluorescence microscopes to analyze the kinetics of the structure. 

Chauvier explained, “We used single-molecule colocalization between an RNAP paused elongation complex (PEC) and the ribosome — one fluorescent color for the nascent mRNA emerging from RNAP and one for the ribosome — to track the kinetics of association and dissociation between the two machineries.”

Webster said, “We call the series of ordered, controlled, and interconnected events a ‘molecular mechanism,’ to emphasize how it can be thought of like the complex mechanism inside a clock for example. I am always amazed that it is possible to reconstitute such an exquisite and biologically fundamental process in a test tube. It is particularly exciting now to have the opportunity to use powerful imaging techniques to answer questions that researchers have been interested in for several decades.”

Understanding these fundamental processes holds great potential for developing new antibiotics that target these specific pathways in bacterial protein synthesis. Traditionally, antibiotics have targeted the ribosome or RNAP, but bacteria often find a way to evolve, and mutate to create some resistance to those antibiotics. Armed with their new knowledge, the team hopes to outwit bacteria by cutting off multiple pathways.  

“We know there is an interaction between the RNAP, the ribosome, transcription factors, proteins, and mRNA,” Chauvier said. “We could target this interface, specifically between the RNAP, ribosome, and mRNA, with a compound that interferes with the recruitment or the stability of the complex.”

Although Weixlbaumer initiated the study with no particular application in mind, he underscored the crucial role fundamental research plays in tackling scientific challenges. He said, “Our work is curiosity-driven, understanding very fundamental processes. It’s like repairing a car, If you don’t comprehend how it works first, you can’t even begin to think about how to fix it.”

Having successfully visualized the very first stage in establishing the coupling between RNAP and the ribosome, the team looks forward to further collaboration to find out how the complex needs to rearrange to become fully functional. Weixlbaumer added, “The book is delivered. How do we open to page one and start reading?” 

“This work demonstrates the power of interdisciplinary research carried out across continents and oceans,” said Walter.

Read the Michigan News announcement – Office of the Vice President for Communications, University of Michigan.

The work was supported by grants from the Agence Nationale de la Recherche (France); Zentrales Innovationsprogramm Mittelstand (ZIM) des Bundesministeriums für Wirtschaft und Klimaschutz (Germany); European Research Council; the National Institutes of Health (United States); and the National Science Foundation.

Collaborative New Study: 
M. Webster, A. Chauvier, et. al. Molecular basis of mRNA delivery to the bacterial ribosome, Science, 29 November 2024, http://www.science.org/doi/10.1126/science.ado8476

2021 University of Michigan Study: 
S. Chatterjee, A. Chauvier, S.S. Dandpat, I. Artsimovitch, N.G. Walter, A translational riboswitch coordinates nascent transcription–translation coupling, Proc. Natl. Acad. Sci. U.S.A. 118 (16) e2023426118, https://doi.org/10.1073/pnas.2023426118 (2021).

Read the full story of the 2021 study by Morgan Sherburne, Michigan News.

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Mason Myers
Ph.D. Student
Department of Biological Chemistry, University of Michigan
Medical School

Yan Zhang Lab

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How do you prove, in a laboratory setting studying objects in size just one-thousandth of the diameter of a hair, that something is doing what it is designed to do?

The Walter Lab at the University of Michigan is doing just that, through single-molecule fluorescence imaging and tracking, and recently for a tiny nano engine that might one day be a workhorse that routinely shuttles RNA molecules and other particles to cells.

Nils Walter, Co-Director of the Center for RNA Biomedicine at Michigan, recently partnered with an international team of scientists headed by the University of Bonn in Germany who developed a biohybrid rhythmic pulsing nanomotor constructed from DNA. 

The DNA nanomachine, measuring 70 nm × 70 nm × 12 nm, is driven by the chemical energy of DNA-templated, nucleotide-fuel-consuming RNA transcription to generate a rhythmically pulsating motion of two rigid DNA-origami arms.

Think of a spring-action hand grip trainer, only rather than squeezing them together the handles are actually being pulled together. This is the mechanism that allows the machine to open and close like a little PAC-MAN.

Walter and his co-collaborators Sujay Ray and Robb Welty, a postdoctoral fellow who now serves as facilities manager at the University of Colorado School of Medicine in Aurora, were tasked with quantifying the movement of this minuscule engine, whose work is detailed in the article, “A rhythmically pulsing leaf-spring DNA-origami nanoengine that drives a passive follower,” published today in Nature Nanotechnology.

They developed a single-molecule Förster resonance energy transfer (smFRET) assay, placing fluorescent marker dyes at distinct points on each arm of the motor to monitor their distance over time.

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Then, they introduced nucleotide fuel, and in real-time were able to measure actual changes in arm spacing, thus indicating movement. They proved definitively, via fluorescence imaging, that these nanomachines are actually pulsing the way they were designed to move.

Article cited: Mathias Centola, Erik Poppleton, Sujay Ray, Martin Centola, Robb Welty, Julián Valero, Nils G. Walter, Petr Šulc & Michael Famulok: A rhythmically pulsing leaf-spring DNA-origami nanoengine that drives a passive follower; Nature Nanotechnology; DOI: 10.1038/s41565-023-01516-x, https://www.nature.com/articles/s41565-023-01516-x

Read the University of Bonn press release, 19 October 2023

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Rooted firmly in his lab suite tucked deep within the core of the Pentagon-esque Medical Sciences Research Building (MSRB) complex on the University of Michigan campus, John Prensner, M.D., Ph.D., is focused on bringing to light an area of genomic investigation involving a hive of “worker bees” called noncanonical ORFs (open reading frames), that play a vital role in the regulation of RNA translation in the human genome.

Unlike traditional mRNA sequencing (mRNA-seq) methods which produce an approximate determination of how many RNA transcripts are present and what their structure is, Prensner’s work relies on a next-generation, deep-sequencing-based tool known as ribosome profiling (Ribo-Seq) which allows Prensner and his team to identify ORFs, which are the select portions of RNA molecules that give rise to proteins – essentially coaxing the cell into giving up many more of its secrets.

To tackle this challenge head-on, Presner harnessed an international team of RNA researchers, and presented the results front and center in his paper, What Can Ribo-Seq, Immunopeptidomics, and Proteomics Tell Us About the Noncanonical Proteome?,” published recently in “Molecular & Cellular Proteomics.” Working with experts in protein biology, RNA biology, and gene annotation, Prensner and the larger team codified a set of working principles that can be used to standardize how Ribo-Seq is used to find noncanonical ORFs.

Prensner and his team hope to create a road map for RNA researchers around the world to follow, that would lead them to perform more precise ribosome profiling, and subsequently catapult this valuable tool to the top of the genomic arsenal.

Read more in the recent Health Lab article, “Improvements in human genome databases offer a promising future for cancer research.”

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The discovery of insulin has saved the lives of millions of people with diabetes worldwide, but little is known about the first step of insulin synthesis.

Researchers at the University of Michigan have uncovered part of this mystery. Examining messenger RNAs involved in the production of insulin in fruit flies, they found that a chemical tag on the mRNA is crucial to translating the insulin mRNA into the protein insulin. The alteration of this chemical tag can affect how much insulin is produced.

The study, conducted by researchers Daniel Wilinski and Monica Dus, is published in the journal Nature Structural and Molecular Biology.

An organism carries DNA—its genes—in each cell of its bodies. Genes are blocks of information that get transcribed into proteins via another molecule called messenger RNAs. These mRNAs are photocopies of DNA—leaving the original DNA untouched—that ferry this protein information into the cytoplasm of cells, where protein is synthesized. The mRNAs are decorated with small molecules called “tags.” These tags can modify how RNAs function and how proteins are produced.

“I like to think of RNA as a Christmas tree,” said Wilinski, a postdoctoral researcher in Dus’ lab in the U-M Department of Molecular, Cellular and Developmental Biology. “Christmas trees are beautiful in the wilderness, but when you bring them inside and put ornaments on them, that decoration is what makes you feel like the tree is part of the season. Same thing with RNA. These decorations on RNA really enhance the way RNA is regulated.”

Studying insulin production in humans or mammals is difficult. In humans, the pancreas is situated behind the liver. It doesn’t regenerate well, and it can’t be sampled in live subjects. But in flies, their insulin cells are actually in their brains, function like neurons, and are physically accessible to researchers. In fruit flies, the researchers looked at a tag called RNA N-6 adenosine methylation, or m6A.

To study the m6A tag, the researchers first identified the RNAs that have the tag. Then they labeled insulin cells with a fluorescent molecule, and used confocal microscopy to visualize how much insulin is produced by the insulin cell. They did this under two conditions: first, they knocked out the m6A enzyme, responsible for decorating the mRNA with m6A tags, in insulin cells. Second, they removed the m6A tags by using CRISPR, a technology used to edit DNA, to mutate the modified As.

In both cases, the flies’ ability to produce insulin was greatly reduced.

“We found that this photocopy of the DNA for insulin, this mRNA, had a specific tag that, when it is present, a ton of the insulin hormone is made,” said Dus, associate professor of molecular, cellular and developmental biology. “But without the signal, flies had much less insulin and developed hallmarks of diabetes.”

This chemical tag is conserved—or unchanged—in fish, mice and humans.

“So it’s likely that insulin production is also regulated through this kind of mechanism in humans,” Wilinski said. “There is an obesity and diabetes epidemic not just in the United States, but across the world. Our finding is another bit of evidence about how this disease happens.”

Dus says the discovery fleshes out the understanding of the biology of insulin and the physiology of diseases of energy homeostasis. Low levels of chemical tags have been observed in people with Type 2 diabetes. Restoring the levels of these tags may also help with combating diabetes and metabolic disease, she says.

“We have known about insulin as a treatment for a hundred years. We have discovered so much about how insulin is made,” Dus said. “But we know so little about the very basic molecular biology of insulin and how it is regulated. That’s why I think this work is important—it refocuses on insulin, the gene and all the things we still have to discover about it.”

Story by Morgan Sherburne, Michigan News

Monica Dus, Ph.D., is a member of the Center for RNA Biomedicine and an Associate Professor with Tenure in the Department of Molecular, Cellular, and Developmental Biology at the University of Michigan.

Daniel Wilinski, Ph.D., is an RNA Featured Researcher with the Center for RNA Biomedicine; and Postdoctoral Fellow and Principal Investigator/Faculty, Dr. Monica Dus, in the Department of Molecular, Cellular, and Developmental Biology in the College of Literature, Science and the Arts at the University of Michigan.

Paper Cited:
“N⁶-adenosine methylation controls the translation of insulin mRNA,” Daniel Wilinski, Monica Dus, Nature Structural & Molecular Biology, 7/24/2023, DOI: https://doi.org/10.1038/s41594-023-01048-x

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A University of Michigan team of biochemists, led by Kristin Koutmou, Ph.D., and Markos Koutmos, Ph.D., Assistant Professors in the Department of Chemistry and Department of Biophysics, is reframing the understanding of the biology of a class of enzymes called Pseudouridine Synthases (Pus enzymes). These enzymes modify many types of RNAs, and the Koutmou and Koutmos Labs’ research brings new insights into the selection principles that guide modification incorporation. Their results are published in the Proceedings of the National Academy of Sciences (PNAS).

This novel understanding of pseudouridine biology could have important therapeutic implications because the dysregulation of Pus enzymes is linked to inherited diseases impacting muscle and brain function, such as progressive mitochondrial myopathy and sideroblastic anemia (MLASA). Furthermore, these enzymes also catalyze pseudouridine incorporation into RNA viral genomes, including that of SARS-CoV-2. As such, Pus enzymes present a potential new target for the development of therapeutics.

Since RNAs are central to the protein synthesis machinery, its chemical modifications can alter how fast and/or how accurately proteins are made. These modifications can have many consequences for cellular health, overall cellular adaptation, and cellular regulation.

This new PNAS publication investigates one of the most common RNA modifications, pseudouridine, which is often found in the mRNA region decoded by the ribosome. Since the 1960s, the enzymes that incorporate pseudouridine have been known to target transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). In 2014, it was discovered that some Pseudouridine Synthases also modify mRNAs, which are structurally very different from tRNAs and rRNAs. This discovery opened the question of understanding how Pus enzymes target so many different types of RNAs.

In this publication, the Koutmou and Koutmos labs teamed together to look at Pseudouridine Synthase 7

(Pus7), one of the main enzymes responsible for adding pseudouridine into mRNAs. To establish a structural basis for how RNA targets are recognized by Pus7, Markos Koutmos and Meredith Purchal, a graduate student in the Program in Chemical Biology, obtained a molecular-level picture of the yeast enzyme using X-ray crystallography. Their X-ray structure revealed that while the core of the enzyme is very similar to the bacterial homologue, Pus7 possesses extra peripheral eukaryotic insertions that might be important for the enzyme to recognize its broad set of mRNA and non-coding RNA targets.

Based on their structure and available data on similar enzymes, the team hypothesized that Pus7 selected its RNA targets by recognizing specific folded structures. “We were totally wrong,” said Koutmou. “As we performed these studies, we realized that this enzyme would modify pretty much anything that had a short consensus sequence, regardless of the RNA structure.” These results established that, to their surprise, it is not RNA structure that governs pseudouridine incorporation. This was initially confounding because Pus7 modifies its consensus sequence only 2% of the time in cells. Dr. Koutmou remarked that “As scientists, it was very frustrating because we were unable to make it not modify! These results certainly made us revisit our hypothesis.”

From the tube to the cell
What, then, makes Pus7 modify such a limited number of the possible RNAs? Unlike when purified and studied in vitro, RNAs in the cell are almost never alone. Being super negatively charged, many proteins and other molecules bind to them, potentially occluding the consensus sequence or stabilizing RNA secondary structures that render the consensus sequence inaccessible. This made the Koutmou and Koutmos teams hypothesize that Pus7 selects its targets based upon the accessibility of these sequences.

This idea launched a series of temperature-dependent and modelling studies demonstrating that Pus7 more frequently and rapidly modifies RNAs with accessible consensus sequences. These results fit with other studies showing that when exposed to heat stress, Pus7 relocalizes from the nucleus into the cytoplasm where it modifies > 200 additional RNA targets. The change in localization increases the local abundance of Pus7 enzymes in the cytoplasm, where, due to the heat shock, the enzyme is more likely to encounter mRNAs with Pus7 exposed consensus sequences. These changes are not permanent and occur in response to transient stress.

The Koutmou and Koutmos teams’ results bring a fresh perspective to understanding how some Pseudouridine Synthases might recognize their substrates by demonstrating that Pus7 substrate selections rely heavily on accessibility to the RNA targets — as opposed to a specific secondary structure. “This is really a reframing of how we think about the strategies used by this class of enzymes to select substrates,” concluded Koutmou.

The flexibility in Pseudouridine Synthase-mRNA substrate selection could be an important process for the adaptation and fitness of the cell, by which it can quickly change the protein synthesis without having to permanently change the DNA. Additional research will further explore these potential adaptive mechanisms.

Kristin Koutmou, Ph.D., is the Seyhan N. Ege Assistant Professor of Chemistry, Department of Literature, Science and the arts, at the University of Michigan.

Markos Koutmos, Ph.D., is a member of the Executive Committee for the Center for RNA Biomedicine and Assistant Professor of Chemistry and Biophysics, Department of Literature, Science and the arts, at the University of Michigan.

Written by: Elisabeth Paymal

Paper cited:
“Pseudouridine synthase 7 is an opportunistic enzyme that binds and modifies substrates with diverse sequences and structures,” Meredith K. Purchal, Daniel E. Eyler, Mehmet Tardu, Monika K. Franco, Megan M. Korn, Taslima Khan, Ryan McNassor, Rachel Giles, Katherine Lev, Hari Sharma, Jeremy Monroe, Leena Mallik, Markos Koutmos and Kristin S. Koutmou, Proceedings of the National Academy of Sciences, 1/25/2022, DOI: 10.1073/pnas.2109708119

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Sami Barmada, M.D., Ph.D.,

In this article, Barmada and his team are interested in autophagy activity, a pathway responsible for mediating the breakdown of cellular proteins and organelles. Autophagy can be compared to a cellular cleaning service, and its dysfunction is associated with many diseases including cancers and neurodegenerative diseases.

Although autophagy plays an important role in cellular biology, to this day, methods to accurately measure its activity are limited and somewhat unreliable. The Barmada team developed a novel biochemical technique that uses protein fluorescent tags inserted into the genome via CRISPR Cas9. This method enables accurate and sensitive assessments of autophagy in living cells by optical pulse labeling, a noninvasive approach that can be used in living cells

“Autophagy has received a great deal of attention because of its therapeutic implications for neurodegenerative and other age-related conditions,” says lead author Dr. Barmada. “Even so, our ability to accurately track autophagy activity or flux has been severely limited by the available tools. Here, we leveraged CRISPR/Cas9 to label an autophagy-related protein in human cells, allowing us for the first time to actually see autophagy in action, and measure flux in a quantitative and reliable fashion.”

With this reliable assay, the team has tested 30,000 drug compounds from four chemical libraries to measure their modulator effect on autophagy. The team also studied the therapeutic potential of autophagy induction in several distinct neuronal models of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The scientists found that the induction of autophagy has opposite effects for different ALS/FTD subtypes.

This novel assay opens the door to testing the effect of many more drugs that either inhibit or stimulate autophagy. This technique can also be adapted to study RNA methylation in ALS and FTD.

“Importantly, the approach used here can be applied to any protein of interest, whether it is a marker of a critical pathway such as autophagy, or itself linked with the development of a disease,” notes Dr. Barmada. “Moreover, in combination with human induced pluripotent stem cells, this technique enables the study of both protein synthesis and degradation not just in immortalized cells, but in specific cell types affected by myriad diseases.”

Sami Barmada, M.D., Ph.D., is Angela Dobson Welch and Lyndon Welch Research Professor of Neurology, Department of Neurology, at the University of Michigan Medical School.

Nathaniel Safren, Ph.D., is Research Assistant Professor of Neurology at Northwestern University, and previously a research scientist at U-M.

Paper cited:
“Development of a specific live-cell assay for native autophagic flux,” Nathaniel Safren, Elizabeth M. Tank, Ahmed M. Malik, Jason P. Chua, Nicholas Santoro, Sami J. Barmada, Journal of Biological Chemistry, Volume 297, Issue 3, 101003, September 2021, DOI: https://doi.org/10.1016/j.jbc.2021.101003

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Sara Aton, Associate Professor in the Department of Molecular, Cellular, and Developmental Biology, and James Delorme, a recent U-M neuroscience graduate student, hypothesized that both a learning event and subsequent sleep (or sleep loss) would impact mRNA translation. Most prior work on the effects of sleep on mRNAs have focused on transcripts in the neuronal cytosol. However, Drs. Aton and Delorme found that after learning, major changes in RNAs are instead present —almost exclusively— on ribosomes associated with neuronal cell membranes. These results have been published in the Proceedings of the National Academy of Sciences, in November 30, 2021.*

In this representation, the red background is the cytosol, and ribosomes are in light green. tRNAs are the purplish blue blobs. Some tRNAs are in the cytosol and others are bound to the green ribosomes. The mRNAs are represented in yellow. The thin purple strand coming out the other side of the ribosomes (and into the ER lumen) is the protein. The big thick black lines in the bottom left corner represents the lipid bilayer of the ER membrane. (Image credit: Sara Aton)

The team first applied a commonly used biochemical method that homogenizes and centrifuges the hippocampal tissue, to separate the cytosol (the aqueous component of the cytoplasm of acell within which smaller organelles and particles are suspended) from other cellular components that are usually considered “debris” (endoplasmic reticulum, golgi apparatus, cell membrane, etc.). In this study, the authors found that RNA associated with ribosomes in the cytosol varied depending on whether the animals slept or not, confirming prior transcriptomic studies. However, cytosolic ribosomes showed almost no RNA changes depending on prior learning.

“If we had just stopped there, we wouldn’t have found anything that was novel or insightful. We strongly felt that we had to rethink our methodology,” explained Aton. Since it is well known that the endoplasmic reticulum is covered with ribosomes, the machinery that converts RNAs into proteins, Delorme and Aton decided to sequence the RNAs in the other parts of the cell, the “debris,” outside of the cytosol. It is in the less-well-studied membrane-containing cell fraction that they found that many transcripts were affected as a function of prior learning. These modified transcripts also differed significantly whether the animals had been allowed to sleep following the learning – allowing a new memory to be stored – or if they had been sleep-deprived. These unexpected results open the door to many more investigations.

“By looking in those other areas of the cell, we now have the capacity to generate many new hypotheses about what happens at the molecular level when memories are consolidated, and when consolidation is interrupted due to sleep deprivation,” said Aton.

For example, in the animals that slept following learning, Aton and Delorme observed an increase in the abundance of transcripts that encode components of protein synthesis machinery in the membrane fraction of hippocampal neurons. One hypothesis would be to test whether there is indeed an increase in protein production by membrane-associated ribosomes after post-learning sleep.

In addition to mRNAs, the authors also found that learning led to changes in long non-coding RNAs’ association with neuronal membrane-bound ribosomes. These could play a role in regulating the translation of other transcripts, which should be investigated. “The cells have developed very elegant mechanisms to fine tune the process from transcription to translation, and long non-coding RNAs could be one of them in this part of the brain,” said Aton.

She further explained by comparing neurons to a large warehouse, with complex logistics that are needed to respond quickly to needs for new proteins in distant cell processes, requiring preparedness and distribution adaptation processes. “Neurons have to deliver the ‘package’ within a reasonable time frame, when it’s needed, no matter how far away that location is. Neurons have evolved to do this, and it is a huge biological question to investigate. It is important to understand how this biology works because – in addition to storing new memories – it impacts regeneration, degeneration, and neurological diseases,” concluded Aton.

This is the second PNAS publication from the Delorme-Aton team’s research. In their first article** (see press release), the team found, in sleep-deprived mice, an inhibitory gating mechanism that could disrupt hippocampal activity and memory consolidation. In contrast, post-learning sleep suppressed the activity of inhibitory interneurons, increased activity among surrounding hippocampal neurons, and improved memory storage.

Papers cited:

* “Hippocampal neurons’ cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep,” James Delorme, Lijing Wang, Varna Kodoth, Yifan Wang, Jingqun Ma, Sha Jiang, Sara J. Aton, Proceedings of the National Academy of Sciences, November 30, 2021, https://doi.org/10.1073/pnas.2108534118

** “Sleep loss drives acetylcholine- and somatostatin interneuron-mediated gating of hippocampal activity, to inhibit memory consolidation,” James Delorme, Lijing Wang, Femke Roig Kuhn, Varna Kodoth, Jingqun Ma , Jessy D. Martinez, Frank Raven, Brandon A. Toth, Vinodh Balendran, Alexis Vega Medina, Sha Jiang, Sara J. Aton, PNAS, June 21, 2021, 10.1073/pnas.2019318118

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Bacteria need to constantly adapt to compete against other species for nutrient sources and to survive against threats such as antibiotics and toxins. In an effort to understand how bacteria control and regulate this adaptation, University of Michigan researchers from the Center for RNA Biomedicine are examining how RNA polymerase—the enzyme that transcribes genetic information from DNA onto RNA—slows during transcription in a process called transcriptional pausing.

They found that a protein called N-utilizing substance A, or NusA, in concert with another control element called a riboswitch, fine-tunes the transcription speed in order to regulate gene expression. Gene expression is the process by which genetic information is converted into the building blocks of the bacterium.

The researchers say their work, published in the Proceedings of the National Academy of Sciences, expands our general understanding of the transcription process in bacteria, and could provide a target for developing new antibiotics.

READ MORE

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