Wang et al. systematically analyzed mitochondria-localized lncRNAs to reveal that RBP-motif recognition drives RNA mitochondrial translocation, leading to the engineering of an RNA mitochondrial targeting sequence (RMTS). Fusing RMTS with sgRNA promotes sgRNA mitochondrial entry, establishing a CRISPR-based mitochondrial DNA editing system that ameliorates heteroplasmic mtDNA mutation diseases.
DNA is the blueprint of life. Genes encode proteins and serve as the body’s basic components. However, building a functioning organism also requires precise instructions about when, where, and how much those components should be produced. This layer of control is carried out by cis-regulatory elements (CREs), which are short stretches of DNA that serve as binding sites for transcription factors and help control the activity of nearby genes, hence are often described as the “switches” and “dials” of genes. Although CREs do not encode proteins themselves, they play a major role in shaping traits, guiding development, and influencing disease risk.
CREs control gene expression through epigenetic mechanisms, such as whether DNA is open and accessible and whether it carries markers associated with active gene regulation. Even small changes in CRE sequences can have substantial effect on gene expression. Until now, scientists have relied on separate experimental methods to study these processes. Some methods identify DNA regions that appear to function as regulatory elements, while others test whether a DNA sequence can activate gene expression. Because these approaches are usually performed independently in different experiments, it has been difficult to directly connect cause and effect or to systematically evaluate the impact of individual changes in the sequence.
To overcome these limitations, the researchers developed an enrichment followed by epigenomic profiling massively parallel reporter assay (e2MPRA), a new technique that builds on their earlier lentiMPRA platform, which enables simultaneous analysis of thousands of CREs by tagging them with unique DNA barcodes that track their activity. e2MPRA takes this technique a step further by also capturing epigenetic states, allowing researchers to directly link what a CRE does with how it does it under identical experimental conditions.
E2MPRA was validated using two large libraries totaling approximately 10,000 sequences: one consisted of synthetic CREs with systematically arranged transcription factor binding sites, and the other contained known CREs in which small DNA changes were introduced to examine how each alteration affected function. For each CRE, the researchers measured three key features: how strongly it activates genes (regulatory activity), whether the surrounding DNA is open and accessible (chromatin accessibility), and whether it carries a chemical “active” mark (H3K27ac modification).
Using this approach, the team demonstrated that different CREs regulate genes in distinct ways. Some primarily boost gene activity without substantially altering DNA structure, while others mainly increase DNA accessibility. The researchers also found that the arrangement and order of the binding sites within a CRE can strongly influence its activity, much like word order can change the meaning of a sentence.
The team then used e2MPRA to examine how tiny DNA changes (as tiny as a single “letter” difference) can disrupt gene regulation. In regions containing the POU5F1::SOX2 binding site, which plays a key role in maintaining stem cell identity, mutations altered not only gene activity but also DNA accessibility and H3K27ac levels.
In contrast, changes in the YY1 binding site showed a more complex behavior: mutations reduced gene activity but increased DNA accessibility. These findings show that DNA variants can influence gene regulation through multiple, overlapping layers rather than through a simple on–off mechanism. ScienceMission sciencenewshighlights.
ObjectivesWe report on a patient with a distinct clinical and neuroradiologic phenotype and a de novo variant in the FTH1 gene. MethodsThe patient was a 25-year-old woman with developmental delay and pontocerebellar hypoplasia, who after years of stable condition visited our hospital at age 20 years because of clinical deterioration. With consent from the patients’ family, we obtained clinical, imaging, and genetic data from the patient’s medical record.
Microglial replacement strategy to treat microgliopathy.
Colony-stimulating factor 1 receptor (CSF1R) gene mutation (I794T) is linked to primary microgliopathy manifesting as leukoencephalopathy.
The researchers define the clinical features of patients carrying the CSF1R p. I794T variant and establish a corresponding knockin mouse model.
The authors demonstrate that knockin mice exhibited hallmark features of CSF1R-related disorder (CSF1R-RD).
They show that Csf1rI792T/+ microglia adopt a disease associated state and that a microglial replacement strategy termed “duplicate-cyclic microglial depletion for transplantation” (DCMDT), mitigates cognitive and neuropathological deficits in CSF1R-RD. sciencenewshighlights ScienceMission https://sciencemission.com/microglia-replacement-18450
Li et al. define the clinical features of patients carrying the CSF1R p. I794T variant and establish a corresponding knockin mouse model. They show that Csf1rI792T/+ microglia adopt a disease-associated state and that a microglial replacement strategy, DCMDT, mitigates cognitive and neuropathological deficits in CSF1R-related disorder.
Researchers at the Cancer Research Institute and the Nano Life Science Institute (WPI-NanoLSI), Kanazawa University, have uncovered a critical mechanism that enables gastric cancer to spread to distant organs. Their study shows that cancer cells stimulate Wnt signaling in surrounding stromal fibroblasts to produce hyaluronan, creating a supportive microenvironment that promotes metastasis. These findings provide new insight into how metastatic tumors establish themselves and suggest promising strategies to prevent gastric cancer progression. The work is published in the journal Nature Communications.
Gastric cancer remains one of the leading causes of cancer-related deaths worldwide, largely because it frequently spreads to other organs such as the liver. While genetic mutations that initiate tumors have been extensively studied, the biological mechanisms that allow cancer cells to colonize new tissues remain poorly understood.
“Wnt signaling”—a pathway essential for stem cell maintenance and tissue regeneration—is often activated in gastric cancer through external ligand stimulation rather than genetic mutation. This study further identifies that Wnt signaling in the tumor microenvironment also plays a crucial role in disease progression.
A wealthy family fighting its own disease boosted research on a little-studied brain protein, progranulin. Can it spur new dementia treatments?
Bluefield investigators, and eventually drug companies, saw something compelling about FTD-GRN, the form of the condition Alice had. In other genetic neurodegenerative disorders, such as familial Alzheimer’s and Huntington disease, mutations spark the production of toxic proteins, generating complex cascades of pathology. But the culprit mutations driving FTD-GRN block progranulin production, leaving carriers with less than half as much of the protein as noncarriers. Many dementia researchers came to describe FTD-GRN as a “low-hanging fruit” among neurodegenerative diseases, using words such as “intuitive” and “tractable” to characterize its biology. The solution seemed obvious: A treatment just needed to raise progranulin levels in the brain.
Fueled in part by that confidence, six clinical trials have been launched to test progranulin-boosting therapies in FTD-GRN. Companies also hope the anti-inflammatory properties of a progranulin-boosting agent could help in Parkinson’s disease, Alzheimer’s, amyotrophic lateral sclerosis (ALS), and FTD caused by other mutations or without a known genetic cause.
All has not gone according to plan, however. In October 2025, a landmark phase 3 clinical trial of a progranulin-boosting drug in people with FTD-GRN did not keep their disease from progressing. In February, a small trial of a gene therapy delivering a healthy copy of GRN to the brain was halted, also for lack of effect.
Researchers at Washington University in St. Louis have developed a novel cell therapy for Alzheimer’s disease using genetically modified astrocytes — the brain’s most abundant cells. By equipping these cells with a chimeric antigen receptor (CAR), scientists enabled them to specifically target and clear beta-amyloid plaques, the toxic protein deposits that accumulate in brain tissue and drive neurodegeneration. In mouse trials, a single injection prevented plaque formation in young healthy rodents and reduced existing plaque levels by half in older mice. While the approach is still being refined to minimize side effects and must be evaluated for human safety, it holds promise both as a preventive measure and as a treatment at various stages of Alzheimer’s. The same technology may eventually be adapted for cancer therapy by reprogramming the cells to target tumor markers.
Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by progressive amyloid accumulation followed by tau-mediated neurodegeneration. Despite advances in anti-amyloid immunotherapies, important limitations remain, highlighting the need for new therapeutic strategies. Here, we introduce anti-amyloid chimeric antigen receptors expressed in astrocytes (CAR-A) and validate their function in vitro. We show that two CAR-A designs reduce amyloid and associated pathology after plaque formation and prevent early plaque deposition in vivo. Single-nucleus RNA sequencing shows that CAR-A treatment induces a distinct glial response to amyloid pathology involving coordinated activity of astrocytes and microglia. Each construct additionally elicits distinctive, receptor-specific effects in astrocytes or microglia.
Solid tumor antigen heterogeneity is a major challenge for cancer immunotherapies, including chimeric antigen receptor (CAR) T cells. Unlike CD19 for B cell malignancies, no target with pan-cellular expression in solid tumors and absence in normal vital cells has been identified. CD70 is a promising candidate, physiologically confined to immune cell subsets and aberrantly expressed in many cancers. We show that heterogeneous CD70 expression in tumors is epigenetically regulated, ranging from high to very low in individual cells, appearing negative by conventional detection methods. Using a highly sensitive CD70 receptor, HLA-independent T cell (HIT) receptor coexpressing CD80 and 4-1BBL for costimulation, we efficiently eliminated CD70-heterogeneous tumors that evade prototypic CAR T cells. These findings provide a potential strategy to treat a broad range of solid tumors.
Protein activity can be precisely regulated via subtle changes in temperature using heat-sensitive switches. Underlying this capability is a novel modular design strategy developed by researchers at the Institute of Pharmacy and Molecular Biotechnology of Heidelberg University. The strategy allows the integration of sensory domains in various proteins regardless of function or spatial structure.
This new approach in the field of thermogenetics is broadly applicable and opens up new possibilities for precise, non-invasive control of different cellular processes. It was developed by a research team led by Prof. Dr. Dominik Niopek and Dr. Jan Mathony and is published in Nature Chemical Biology
Proteins are the molecular machines of the cell. They regulate nearly all vital processes and their responses are highly dynamic. To better understand these processes and their chronological sequence, scientists need tools that can be used to change individual parameters precisely and in a controlled manner. The most suitable proteins are those that can be turned on and off like technical devices. Especially attractive in this context are heat-sensitive protein switches that tightly regulate the temperature spatiotemporally and are able to deeply penetrate tissue or complex biological samples as a signal.