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A revolutionary map of the fly brain could transform neuroscience

Wednesday, October 2, 2024

Researchers have developed a groundbreaking new resource—the, described today in the journal —that maps every neuron and synaptic connection in the central brain of Drosophila melanogaster, or the fruit fly. Totaling over 130,000 neurons and 30 million synaptic connections, this revolutionary tool will expedite inquiry into how the brain works and expand the questions that can be asked.

“The importance of this cannot be understated, because it really just drastically changes the field,” said Gabriella Sterne, PhD, assistant professor of Biomedical Genetics and Neuroscience at the Del Monte Institute for Neuroscience at the University of Rochester, who contributed to this research as a member of the FlyWire consortium, a group co-led by the MRC Laboratory of Molecular Biology in Cambridge, United Kingdom, Princeton University, the University of Vermont, and the University of Cambridge. “The first time I saw the complexity of the connectome it literally blew my mind because we have been thinking of these circuits in a simplistic manner, but we can now appreciate that they are far more complex than we imagined.”

Researchers will be able to use this resource to untangle complex brain connections and functions, accelerate findings, inform machine learning and artificial intelligence, and improve our understanding of the human brain. “The connectome makes it easier to uncover general and fundamental principles that govern neural circuit function. Discovering such principles in a relatively simple brain will inform the search for similar processes in the human brain, potentially leading to unifying theories of brain function,” Sterne explained. “Once we understand the computations that neural circuits are performing in a healthy brain, we can start to ask how circuit function is disrupted in disease.”

New Research Offers Hope for Preventing Age-Related Blindness

Wednesday, October 2, 2024

Age-related macular degeneration (AMD) is a leading cause of irreversible vision loss in the United States. Despite existing treatments, the underlying causes of this disease and effective therapies remain elusive. New research published in the journal  provides important insights into the cellular mechanisms behind AMD and offers potential avenues for new treatments.

"Current treatments for AMD have limited efficacy and often come with significant side effects," said Ruchira Singh, PhD, with the University of Rochester Flaum Eye Institute and Center for Visual Sciences, and lead author of the study. "Our research aims to identify novel therapeutic targets that could potentially halt the progression of this disease."

The study utilized human stem cells to model AMD, overcoming the limitations of previous research using animal models. By examining genes associated with both AMD and rarer inherited forms of blindness called macular dystrophies, the researchers identified a key protein involved in the early stages of the disease.

The retinal pigment epithelium (RPE), a layer of cells at the back of the eye, plays a crucial role in AMD. Over time, deposits of lipids and proteins, known as drusen, accumulate in the RPE. These deposits are often an early indicator of AMD.

BGG Student Xiurui Lyu Successfully Defends Their Thesis!

Friday, July 12, 2024

​On Wednesday July 10th, Xiurui Lyu successfully defended his thesis. Xiurui is a medical school graduate from Nanjing Medical University who began his doctoral studies in the BGG program in 2020. Xiurui Lyu pursued his thesis research in the laboratory of Dr. Laurie A. Steiner M.D. After completing his doctorate, Xiurui plans to continue his research in the Steiner Lab with a postdoc appointment.

Congratulations Xiurui!

Title: ‘Regulation of transcriptional pausing is key to erythropoiesis’
Abstract: Regulation of RNA polymerase II (RNAPII) activity is an essential process that governs gene expression; however, its contribution to the fundamental process of erythropoiesis remains unclear. hexamethylene bis-acetamide inducible 1 (HEXIM1) regulates RNAPII activity by controlling the location and activity of positive transcription factor β. We identified a key role for HEXIM1 in controlling erythroid gene expression and function, with overexpression of HEXIM1 promoting erythroid proliferation and fetal globin expression. HEXIM1 regulated erythroid proliferation by enforcing RNAPII pausing at cell cycle check point genes and increasing RNAPII occupancy at genes that promote cycle progression. Genome-wide profiling of HEXIM1 revealed that it was increased at both repressed and activated genes. Surprisingly, there were also genome-wide changes in the distribution of GATA-binding factor 1 (GATA1) and RNAPII. The most dramatic changes occurred at the β-globin loci, where there was loss of RNAPII and GATA1 at β-globin and gain of these factors at γ-globin. This resulted in increased expression of fetal globin, and BGLT3, a long noncoding RNA in the β-globin locus that regulates fetal globin expression. GATA1 was a key determinant of the ability of HEXIM1 to repress or activate gene expression. Genes that gained both HEXIM1 and GATA1 had increased RNAPII and increased gene expression, whereas genes that gained HEXIM1 but lost GATA1 had an increase in RNAPII pausing and decreased expression. Together, our findings reveal a central role for universal transcription machinery in regulating key aspects of erythropoiesis, including cell cycle progression and fetal gene expression, which could be exploited for therapeutic benefit.

The balance between kinase and phosphatase activity is a key regulator of RNAPII activity. The Integrator Complex (INT) is a modular and multi-subunit machinery that binds to paused RNAPII and promotes promoter-proximal termination. INT is highly expressed in maturing erythroid cells, although little is known about the function of INT during erythropoiesis. Disruption of INTS8 significantly impaired erythroid proliferation and viability. It also delayed erythroid maturation, evident by delayed GPA expression, less mature morphology, and lower rates of benzidine positivity. Moreover, INTS8 disruption led to a decline in erythroid colony-forming ability and decreased expression of alpha and beta globin. Together these data indicate that INT function is essential for erythropoiesis. To delineate the genomic targets of INT we performed CUT&RUN for INTS1 during maturation of erythroid culture following CD36 selection, corresponding to the basophilic and polychromatic stages of erythroid maturation. Approximately 50% of sites of INT occupancy were located at transcription start sites at both time points. Motif analyses of sites of INTS1 occupancy were enriched for transcription factors involved in signaling, including STAT5, and INTS1 was present at several known STAT5 target genes including MYC and CCNB1. Interestingly, ~74% of genes with stably paused RNAPII, as indicated by a pausing index (PI) >4, were occupied by INTS1. Further, the level of INTS1 occupancy was significantly higher at genes with a PI >4 than genes with PI <4. The genomic occupancy of INTS increased from day 7 to day 9. Transcription start sites that gained INTS1 occupancy during maturation lost RNPII, suggesting a role for INT in promoting RNAPII eviction at these loci. Collectively, our findings identify a critical role for INT in governing erythroid maturation and gene expression, and provide novel insights into the transcriptional regulation of erythropoiesis.

Turns out—male roundworms are picky when choosing a mate, new research finds

Monday, March 11, 2024

A piece of rotting fruit is likely covered in hundreds if not thousands of microscopic roundworms, including C. elegans—a popular experimental model system for studying neurogenetics. With a lifespan of only a few weeks, C. elegans must reproduce quickly and often. The species is made up of hermaphrodites and males. The hermaphrodites have female bodies, can self-fertilize, and can mate with males. Recent research from of the Portman Lab at the Del Monte Institute for Neuroscience at the University of Rochester, found the males do not mate indiscriminately—they are selective about things like age, mating history, and nutrition.

“We have been aware of many of the mating cues this species uses, but this is the first time we have been able to look at them together to learn more about what they tell a male about a potential mate,” Doug Portman, PhD, professor of Biomedical Genetics said. “Assessing a mate’s characteristics seems to be something that only the male does. Understanding sex differences in C. elegans gives us important insight into how genes influence the function of neurons and circuits to guide innate behaviors—like choosing a mate.”

C. elegans is an invaluable tool to neuroscience research. Scientists have identified all of the roundworm’s neurons—there are only a few hundred of them—and the connections between its neurons have also been mapped, providing a model for understanding how neuronal circuits work in humans. It is well understood that mating is a priority for male C. elegans. Previous research out of the Portman lab found male C. elegans will suppress the ability to locate food in order to find a mate.

In a study out today in , the Portman lab conducted experiments to observe how roundworms in petri dishes choose between potential mates. They discovered that the male worms used diverse chemical (pheromones) and physical (touch) signals to determine the sex, age, nutritional health, and mating history of the hermaphrodites. Researchers found male worms can determine a hermaphrodite’s nutritional status—whether it is healthy or food-deprived—and whether it has previously mated. When given a choice, the males showed preference toward hermaphrodites that have not previously mated with another male and are nutritionally healthy. However, once a hermaphrodite is a few days old—approaching middle age for a worm—it puts out a powerful sex pheromone that attracts males over long distances. That is because it starts to run out of its own sperm, so finding a mate becomes a more important.

BGG Student Shen Zhou Successfully Defends Thesis

Friday, January 12, 2024

​BGG Student Shen Zhou held his thesis defense on Wednesday, January 10th. Shen Zhou came to the University of Rochester in 2015. Shen pursued his thesis research in a mentorship with Dr. Mark Noble, Ph.D. After earning his doctorate in the BGG program Shen plans to earn a master’s of data science here at the UR’s School of Arts, Sciences & Engineering. We wish Shen the best on his future endeavors. You may read Shen’s thesis abstract below.

Congratulations Shen!

Thesis Title: The study of c-Cbl in Clear Cell Sarcoma.
Thesis Abstract: Clear Cell Sarcoma (CCS) is a rare malignant tumor that has a unique gene fusion of the Activating Transcription Factor (ATF-1) and the Ewing’s sarcoma break point region 1 (EWSR1), producing the fusion protein of EWSR1/ATF1 that promotes cells proliferation. CCS is insensitive to chemotherapeutic agents. The current mainstream treatment for CCS is surgical resection and radiation therapy, which still have poor prognosis and high tumor recurrence rate. c-Cbl is a tumor suppressor gene. Our lab showed that Maprotiline (MPT) + Tamoxifen (TMX) can effectively inhibit the growth of Glioblastoma (GBM) and TMX resistant human breast cancer by restoring c-Cbl phosphorylation and the Redox/Fyn/c-Cbl (RFC) pathway. To test how TMX+MPT can affect CCS, we used TMX+MPT to treatment CCS. We found that TMX+MPT can suppress CCS growth. The suppression of this growth is c-Cbl dependent. In addition, the treatment of TMX+MPT can restore c-Cbl phosphorylation and downregulate multiple mitogenic proteins including receptor tyrosine kinase p-c-Met. Cool-1/ßpix seems to be inhibiting c-Cbl by binding to c-Cbl, as MPT can disrupt the interaction between c-Cbl and Cool-1/ßpix. A higher expression level of c-Cbl-Cool-1/ßpix may also predict a better cell response to the treatment of TMX+MPT. To summarize, by the reactivation of c-Cbl, we use TMX+MPT to effectively suppress the growth of CCS. Our findings provide a new insight into the role of c-Cbl and the treatment of this rare malignant tumor.