Publication Highlights

Neurons result from a highly complex and unique series of cell divisions. For example, in fruit flies, the process starts with stem cells that divide into mother cells (progenitor cells), that then divide into precursor cells that eventually become neurons.

A team of the University of Michigan (U-M), spearheaded by Nigel Michki, a graduate student, and Assistant Professor Dawen Cai in the department of Cell and Developmental Biology in the Medical School and in Biophysics in the College of LS&A, identified many genes that are important in fruit flies’ neuron development, and that had never been described before in that context.

Figure to the left: Neurons in the fruit fly brain are made by passing through various differentiation states, and are segregated into unique subtypes based on the age and cell division number of their mother cell (progenitor). The complexity of this process is modelled in the diagram above. Different RNAs play a role in these neuron formation steps. This study identifies many RNAs that were not previously known to be involved in these processes, and helps us better understand how this complex neuron-generation process works at the molecular level.

Since many genes are conserved across species such as between fruit flies (Drosophila), mice, and humans, what is learnt in flies can also serve as a model to better understand other species, including humans. “Now that we know which genes are involved in this form of neurogenesis in flies, we can look for them in other species and test for them. We work on a multitude of organisms at U-M and we’ve the potential to interrogate across organisms,” explains Michki. “In my opinion, the work we did is one of the many pieces that will inform other work that will inform disease,” adds Michki. “This is why we do foundational research like this one.”

Flies are also commonly used in many different types of research that might benefit from having a more comprehensive list of the fly genes with their associated roles in neuron cell development.

[Read more…] about U-M RNA scientists identify many genes involved in neuron development

ANN ARBOR—To better understand how RNA in bacteria gives rise to protein—and along the way, target these processes in the design of new antibiotics—researchers are turning their attention to the unique way this process happens in bacteria.

In eukaryotic cells, transcription (the process by which information in a DNA strand is copied into messenger RNA) and translation (the process by which a protein is synthesized by the ribosome from the mRNA) are two successive steps. In bacteria, they occur simultaneously: As the RNA is being synthesized by RNA polymerase, the ribosome comes in to make the proteins.

This synchronicity allows for so-called “transcription-translation coupling,” wherein the first ribosome can immediately follow and couple with the transcribing RNA polymerase. It is a new area of research that promises to bring insights into processes unique to bacteria that could be targeted with great specificity in the design of antibiotics.

Now, University of Michigan researchers have directly observed previously hidden RNA regulatory mechanisms within such couplings. The results, spearheaded jointly by postdoctoral fellows Surajit Chatterjee and Adrien Chauvier of the U-M Department of Chemistry and the U-M Center for RNA Biomedicine, are published in the Proceedings of the National Academy of Sciences.

The new results promise to have important implications for the future design of antibiotics that could target the coupling mechanism instead of targeting the transcription or translation processes separately.

Caption: The 30S subunit of the ribosome can dynamically bind to the nascent mRNA as soon as its binding site emerges from the RNAP. Transcription factors and translation initiation factors assist in the initial binding and retention of the 30S subunit on the mRNA, resulting in the stabilization of an early initiation complex. During translation, the ribosome can follow the leading RNAP, establishing transcription-translation coupling and maintaining optimal transcription speed. In the presence of the ligand preQ₁, transcription-translation coupling is disrupted, surprisingly leading to slow transcription.

[Read more…] about RNA holds the reins in bacteria: U-M researchers observe RNA controlling protein synthesis

In our September 2020 issue of RNA Translated, 2020 the year of the RNA virus, we presented how University of Michigan (U-M) Center for RNA Biomedicine’s scientists pivoted their research to address the COVID-19 pandemic. One of them is Dr. Chinnaiyan and his team of prostate cancer researchers who focused on two proteins that are involved in giving access to the virus into a host cell. The production of these two proteins is regulated by male hormones. With J. Sexton from the U-M Center for Drug Repurposing, the collaborators looked at repurposing well-known drugs used in prostate cancer to block a receptor for male hormone, and prevent the coronavirus from entering a host cell.

“We hope that these findings may partly explain why males have higher hospitalization and mortality rates than females, and also suggest that transcriptional inhibition of key host factors may have potential in preventing or treating COVID-19. A number of clinical trials in COVID-19 patients have been initiated with drugs that were previously used to treat prostate cancer,” says Dr. Chinnaiyan.

The results from the current study are published in the January 5, 2021, Proceedings of the National Academy of Sciences.

Referenced article:
Targeting transcriptional regulation of SARS-CoV-2 entry factors ACE2 and TMPRSS2
Yuanyuan Qiao, Xiao-Ming Wang, Rahul Mannan, Sethuramasundaram Pitchiaya, Yuping Zhang, Jesse W. Wotring, Lanbo Xiao, Dan R. Robinson, Yi-Mi Wu, Jean Ching-Yi Tien, Xuhong Cao, Stephanie A. Simko, Ingrid J. Apel, Pushpinder Bawa, Steven Kregel, Sathiya P. Narayanan, Gregory Raskind, Stephanie J. Ellison, Abhijit Parolia, Sylvia Zelenka-Wang, Lisa McMurry, Fengyun Su, Rui Wang, Yunhui Cheng, Andrew D. Delekta, Zejie Mei, Carla D. Pretto, Shaomeng Wang, Rohit Mehra, Jonathan Z. Sexton, and Arul M. Chinnaiyan, PNAS January 5, 2021 118 (1) e2021450118; first published December 11, 2020; https://doi.org/10.1073/pnas.2021450118

The observation of single biomolecules in real-time is crucial for our understanding of the cellular biology that is assembled from these molecules, be they DNA, RNA or protein. The recent development of an array of tools and techniques for single-molecule analysis allows studies at an extremely small scale (nanometers, or 10^-9 meters) over short periods of time (from a few milliseconds to a second).

However, until now, most of such observations required tedious and time-consuming manual data processing of thousands of single molecules.  A team of University of Michigan (U-M) Department of Chemistry and Department of Physics scientists, spearheaded by graduate students Jieming Li, now Ph.D. in Chemistry, and Leyou Zhang, now Ph.D. in Physics, developed a deep learning algorithm to analyze data emerging from a single molecule microscope. The results from this collaboration are published in Nature Communications (November 2020).

Illustration: Deep learning assisted single molecule fluorescence microscopy data analysis [Read more…] about Machine learning expands single-molecule analysis accuracy and accessibility

A cross-disciplinary team of scientists from the University of Michigan (U-M) has developed a biochemical technique that successfully measures the number of individual protein molecules present in blood at low concentrations. These findings are published in the Proceedings of the National Academy of Sciences (PNAS), September 2020.

The scientists developed special antibody probes that repeatedly bind to and then release the target protein. With a single-molecule fluorescence microscope, they measured the number of times and for how long the repeated binding events occurred.

[Read more…] about “Kinetic fingerprinting” of single protein molecules to find the biomarker needle in the haystack

By Elisabeth Paymal

A team of scientists associated with the University of Michigan Center for RNA Biomedicine discovered unexpected cellular adaptation mechanisms in response to dehydration. The observed protein reaction has never been reported before.

The research began while observing processing bodies (P-Bodies), which are membrane-less organelles (MLO) involved in RNA degradation in human cells. The team found that, in response to osmotic changes provoked by high saline or sugar concentrations and subsequent dehydration, many proteins within the cell form aggregates similar to P-Bodies. The reaction takes only a few seconds and is reversible.

This phenomenon is distinct from the well-known integrated stress response that leads to the formation of stress granules, another type of membrane-less organelle that aggregates over several minutes.

“At the fundamental level, our work has unraveled a new paradigm for subcellular (membrane-less) organization and rapid stress response,” says Sethu Pitchiaya, a biophysical chemist, one of two shared first authors and a co-senior author on this publication.

Illustration: A pink cell experiences a gradient of salt levels, depicted as crystals. In response to changes in external salt levels, “clouds” of protein form by phase separation. These protect against the dehydrating effects of salt. (Illustration, Elisabeth Paymal) [Read more…] about Stressed cellular proteins break social distancing rules

Before and after treatment

Over half of our genomes are made of repeating elements within DNA. In rare cases, these repeats can become unstable and grow in size. These repeat “expansions” cause neurodegenerative diseases such as ALS and Dementia as well as learning disorders and autism in Fragile X syndrome. Research to date has focused on how these expanded repeats cause disease, but little attention has been given to the repeats themselves and whether they might have normal functions in genes.

By focusing on the biology of healthy nerve cells, a team from the University of Michigan Department of Neurology found that repeats in the gene that causes Fragile X Syndrome normally regulate how and when proteins are made in neurons. This process may be important for learning and memory in these nerve cells and potentially in people. “The repeats function like a switch, slowing down protein production and then quickly turning things back on,” explains Peter Todd, MD., Ph.D., and Principal Investigator of this research.

[Read more…] about Publication in Nature Neuroscience: Disease-causing Repeats Help Human Neurons Function