Category: 7. Science

BUFFALO, N.Y. — Look inside a brain cell with Huntington’s disease or ALS and you are likely to find RNA clumped together.

These solid-like clusters, thought to be irreversible, can act as sponges that soak up surrounding proteins key for brain health, contributing to neurological disorders.

How these harmful RNA clusters form in the first place has remained an open question.

Now, University at Buffalo researchers have not only uncovered that tiny droplets of protein and nucleic acids in cells contribute to the formation of RNA clusters but also demonstrated a way to prevent and disassemble the clusters.

Their findings, described in a study published Thursday (July 2) in Nature Chemistry , uses an engineered strand of RNA known as an antisense oligonucleotide that can bind to RNA clusters and disperse them.

“It’s fascinating to watch these clusters form over time inside dense, droplet-like mixtures of protein and RNA under the microscope. Just as striking, the clusters dissolve when antisense oligonucleotides pull the RNA aggregates apart,” says the study’s corresponding author, Priya Banerjee, PhD, associate professor in the Department of Physics, within the UB College of Arts and Sciences. “What’s exciting about this discovery is that we not only figured out how these clusters form but also found a way to break them apart.”

The work was supported by the U.S. National Institutes of Health and the St. Jude Children’s Research Hospital.

How RNA clusters form

The study sheds new light on how RNA clusters form within biomolecular condensates.

Cells make these liquid-like droplets from RNA, DNA and proteins — or a combination of all three. Banerjee’s team has researched them extensively, investigating their role in both cellular function and disease, as well as their fundamental material properties that present new opportunities for synthetic biology applications.

The condensates are essentially used as hosts by repeat RNAs, disease-linked RNA molecules with abnormally long strands of repeated sequences. At an early timepoint, the repeat RNAs remain fully mixed inside these condensates, but as the condensates age, the RNA molecules start clumping together, creating an RNA-rich solid core surrounded by an RNA-depleted fluid shell.

“Repeat RNAs are inherently sticky, but interestingly, they don’t stick to each other just by themselves because they fold into stable 3D structures. They need the right environment to unfold and clump together, and the condensates provide that,” says the study’s first author, Tharun Selvam Mahendran, a PhD student in Banerjee’s lab.

“Crucially, we also found that the solid-like repeat RNA clusters persist even after the host condensate dissolves,” Mahendran adds. “This persistence is partly why the clusters are thought to be irreversible.”

Preventing — and reversing — clusters

The team was first able to demonstrate that repeat RNA clustering can be prevented by using an RNA-binding protein known as G3Bp1 that is present in cells.

“The RNA clusters come about from the RNA strands sticking together, but if you introduce another sticky element into the condensate, like G3BP1, then the interactions between the RNAs are frustrated and clusters stop forming,” Banerjee says. “It’s like introducing a chemical inhibitor into a crystal-growing solution, the ordered structure can no longer form properly. You can think of the G3BP1 as an observant molecular chaperone that binds to the sticky RNA molecules and makes sure that RNAs don’t stick to each other.”

In order to reverse the clusters, the team employed an antisense oligonucleotide (ASO). Because ASO is a short RNA with a sequence complementary to the repeat RNA, it was able to not only bind to the aggregation-prone RNAs but also disassemble the RNA clusters.

The team found that ASO’s disassembly abilities were highly tied to its specific sequence. Scramble the sequence in any way, and the ASO would fail to prevent clustering, let alone disassemble the clusters.

“This suggests our ASO can be tailored to only target specific repeat RNAs, which is a good sign for its viability as a potential therapeutic application,” Banerjee says.

Banerjee is also exploring RNA’s role in the origin of life, thanks to a seed grant from the Hypothesis Fund. He is studying whether biomolecular condensates may have protected RNA’s functions as biomolecular catalysts in the harsh prebiotic world.

“It really just shows how RNAs may have evolved to take these different forms of matter, some of which are extremely useful for biological functions and perhaps even life itself — and others that can bring about disease,” Banerjee says.

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Scientists from the University of Konstanz and Queen Mary University of London have identified a key molecular trigger that facilitates a crucial step in the formation of red blood cells.

The finding could advance research efforts into artificial blood production, the researchers say, though clinical applications remain distant.

The research is published in Science Signaling.

The role of CXCL12 in red blood cell formation

Red blood cell production, known as erythropoiesis, naturally occurs in the bone marrow. Stem cells mature into erythroblasts, which then develop into erythrocytes (red blood cells). In the final phase of this development, erythroblasts expel their nucleus, creating more internal space for hemoglobin – a protein that enables oxygen transport. This process is unique to mammals.

Although much is known about the maturation of stem cells into red blood cells, the mechanism prompting nuclear expulsion was unclear.

The research team, led by Dr. Julia Gutjahr from the Institute of Cellular Biology and Immunology Thurgau at the University of Konstanz, has identified that the chemokine CXCL12 can initiate this step. 

“We discovered that the chemokine CXCL12 found mainly in bone marrow can trigger such nucleus expulsion, albeit in an interplay with several factors. By adding CXCL12 to erythroblasts at the right moment, we were able to artificially induce the expulsion of their nucleus,” said Gutjahr.

Mechanism reveals new function of chemokine receptors

The study found that CXCL12 interacts with red blood cell precursors differently than it does with other cell types. While other cells migrate in response to CXCL12, erythroblasts internalize the molecule, even transporting it into the nucleus. This internal action enhances cell maturation and assists in nucleus expulsion.

The research suggests that chemokine receptors may have intracellular roles in addition to their established function on the cell surface and may inform future techniques for improving the efficiency of artificial blood production.

“Importantly, apart from immediate practical application for the industrial production of red blood cells, our results brought a completely new understanding of cell biological mechanisms involved in erythroblast responses to chemokines,” added senior study author Antal Rot, a professor of inflammation sciences in the William Harvey Research Institute at Queen Mary University of London.

“While all other cells migrate when stimulated by CXCL12, in erythroblasts this signalling molecule is transported into the interior of the cell, even into the nucleus,” Rot continued. “There, it accelerates their maturation and helps to expel the nucleus. Our research shows for the first time that chemokine receptors not only act on the cell surface but also inside the cell, thus opening entirely new perspectives on their role in cell biology,”

Challenges in sourcing cells for artificial blood

Artificial blood production typically starts with stem cells derived from umbilical cord blood or bone marrow. These cells can achieve nucleus expulsion in approximately 80% of cases. However, the limited availability and high demand for these cells makes this approach insufficient for large-scale applications.

Recent advancements in cell reprogramming have allowed for the transformation of other cell types into stem-like cells, which can then be guided to produce red blood cells. Yet, this method is slower and less efficient, with successful nucleus expulsion occurring in only 40% of cases.

“Based on our new findings highlighting the key role of CXCL12 in triggering nuclear expulsion, we can expect that using CXCL12 should bring significant improvement in producing red blood cells from reprogrammed cells,” said Gutjahr.

The research team hopes that new advances aiding large-scale artificial blood production could lead to immediate, meaningful improvements for patients.

“Even though body cells are readily available, the lab-based production process will remain complex. But it would enable the targeted generation of rare blood types, help bridge shortages or allow individuals to reproduce their own blood for specialized treatments in many different diseases,” said Gutjahr.

Reference: Gutjahr JC, Hub E, Anderson CA, et al. Intracellular and nuclear CXCR4 signaling promotes terminal erythroblast differentiation and enucleation. Sci Signal. 2025;18(891):eadt2678. doi: 10.1126/scisignal.adt2678

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