Selected Grantee Publications
- 713 results found
KDM3A Catalyses the Oxidation of Acetyl-Lysine to Hydroxyacetyl-Lysine on Histone H3K9
Belle et al., Nature Chemistry. 2026.
https://pubmed.ncbi.nlm.nih.gov/41986689
Histones play an important role in packaging DNA within a cell’s nucleus. Modifications to histones allow DNA to be accessible to make copies of RNA (transcription) or compact to prevent transcription. In this study, researchers found that enzyme KDM3A, known for removing methyl groups from histones to suppress transcription, was found to also oxidize an acetyl group on histone H3—H3K9ac—to produce a novel modification called Nε-hydroxyacetyl-lysine. This modification is still recognized by the same proteins that bind the standard acetyl group to promote transcription. Using human cell lines, antibodies (proteins that bind to a specific target), and mass spectrometry (technique to identify molecules) methods, researchers confirmed its cellular relevance. These findings reveal an unexpected oxygen-dependent link between histone acetylation and KDM3A enzyme activity, with implications for how cells respond to hypoxia and inhibitors of histone enzymes for cancer treatment. Supported by ORIP (S10OD030286).
Single-Cell Atlas of the Transcriptome and Chromatin Accessibility in the Human Retina
Li et al., Nature Genetics. 2026.
https://pubmed.ncbi.nlm.nih.gov/41578023
Single-cell sequencing (a technique to study the genetic material of an individual cell) has advanced the capability to explore cell diversity within tissues and across disease states. In this study, researchers created the Human Retina Cell Atlas (HRCA). HRCA has single-cell data for 3.9 million human retina cells (nerve tissue at the back of the eye) from 125 donors with various ancestral backgrounds. More than 130 distinct retinal cell types have been identified from analyzing these millions of cells. The researchers modeled how gene expression and chromatin accessibility shift with age, ancestry, and tissue region—factors directly relevant to understanding age-related and population-specific eye diseases. HRCA helps pinpoint genetic factors underlying retinal diseases—including glaucoma and age-related macular degeneration—by improving the mapping of variants (different forms of a gene) linked to genome-wide association studies (a method to determine whether a variant is linked to a trait or disease) and quantitative trait loci (a gene’s location on the chromosome). HRCA is publicly available so that researchers can access the data; advance the understanding of retinal function; and identify biomarkers, diagnostics, and therapies for eye diseases. Supported by ORIP (S10OD023469) and NEI.
Developmental Organization of Sensory and Sympathetic Ganglia
Vong et al., Nature. 2026.
https://pubmed.ncbi.nlm.nih.gov/41922758
The underlying mechanisms of cell fate in developmental biology remain poorly understood. During development, the neural crest (a group of cells in the embryo) transforms into a broad range of cell types—including smooth muscle and ganglia (clusters of nerve cell bodies that help transmit signals in the nervous system). In this study, researchers investigated how neural crest cells transform into sensory and sympathetic ganglia during development. Using CRISPR lineage barcoding (a gene-editing method) in 1-month-old mice (sex not stated), live imaging in quail embryos, and mosaic variant barcode analysis of human tissue (both sexes used), the researchers found that progenitor cells spread along the body axis bilaterally (on both sides). Results showed that FGF signaling played an important role in driving the spread of progenitor cells along the body axis. Data also showed limited overlap between sensory and sympathetic cell lineages. These findings play an important role in understanding the origins of developmental disorders and neural crest–related conditions, such as neuroblastoma. The similarity of findings between the human and mouse models supports the use of preclinical models to develop regenerative therapies that target neural crest molecules. Supported by ORIP (S10OD021644, S10OD026929), NICHD, and NIMH.
In Vivo Base Editing Rescues Liver Pathophysiology and Peroxisome Dysfunction in a Mouse Model of Zellweger Spectrum Disorder
Gao et al., Nature Biomedical Engineering. 2026.
https://pubmed.ncbi.nlm.nih.gov/41981313
Zellweger spectrum disorder (ZSD) is caused by loss-of-function variations in any of 13 PEX genes that encode peroxins. Peroxins are required for the creation of peroxisomes (organelles in cells that convert hydrogen peroxide from normal cell processes into nontoxic products), which are critical for cell signaling and metabolism. ZSD often results in chronic conditions—including cirrhosis and hepatocellular carcinoma (liver cancer). Using a neonatal and 4-week-old mouse model for ZSD, researchers tested a gene-editing strategy to correct the mutation. Results showed that 60% of the pathogenic allele (disease-causing version of a gene) was corrected in the liver. Researchers also tested the gene-editing strategy in patient-derived fibroblasts and observed more than 80% correction of the pathogenic allele. This correction prevented the buildup of toxic products in PEX-mutated peroxisomes. These findings support the use of gene editing to benefit individuals with ZSD and provide a foundation to create precision treatments for peroxisome disorders. Supported by ORIP (R24OD030033, U42OD010921, U54OD020351, U54OD030187), NHGRI, NIAID, and NIGMS.
Adult Canine Pancreatic Organoids Enable Functional Analysis of Pancreatic Epithelial Barrier and Inflammatory Responses
Nakazawa et al., BMC Molecular and Cell Biology. 2026.
https://pubmed.ncbi.nlm.nih.gov/41928078
3D organoids are useful for modeling pancreatic epithelial development, differentiation, and disease. Dogs naturally develop a range of pancreatic diseases—including acute pancreatitis and pancreatic cancer—that mimic the clinical and pathological (disease-causing) features observed in humans. In this study, researchers successfully developed a long-term organoid model for the pancreas from 1.5- to 10-year-old male adult canines that demonstrated a stable ductal phenotype (physical characteristics). The researchers also developed a 2D culture from the organoids and showed that epithelial barrier integrity and function were maintained. This study provides a reproducible protocol for creating ethically accessible and physiologically relevant 3D organoids and 2D cultures of the adult pancreas. This study provides a foundation for future research in pancreatic disease modeling, comparative medicine, and therapeutic strategies. Supported by ORIP (K01OD030515, R21OD031903).
Cognitive Impairment Caused by Compromised Hepatic Ketogenesis Is Prevented by Endurance Exercise
Kelty et al., The Journal of Physiology. 2026.
https://pubmed.ncbi.nlm.nih.gov/39808588
Previous research has demonstrated that endurance exercise improves cognition and is neuroprotective against aging and disease. However, the underlying mechanisms of these benefits remain poorly understood. In this study, researchers determined whether ketones, produced by the liver, mediate endurance exercise–based neuroprotection. Using 6-month-old female rats, researchers found that hepatic ketogenesis (production of ketones by the liver) is required to maintain cognition, synaptic plasticity (connections across brain cells), and mitochondrial (cellular organelles that create energy) function. Results also showed that prolonged endurance exercise prevents nervous system deficiencies caused by insufficient hepatic ketogenesis. These findings establish a link between the liver and brain and demonstrate the importance of understanding how peripheral tissue, such as the liver, regulates brain health. Supported by ORIP (T32OD011126) and NIA.
T-Cell Signaling Pathways, Including Exhaustion, Predominate in Unhealthy Visceral and Subcutaneous Adipose Tissues
Puppala et al., Obesity (Silver Spring). 2026.
https://pubmed.ncbi.nlm.nih.gov/41603630
Adipose tissue (fat) and adipose inflammation—caused by immune cells—are implicated in metabolic (all changes in a cell to produce energy and molecules) health. Previous research shows that visceral (surrounding organs) adipose tissue (VAT) generally is a factor of poor metabolic health, whereas subcutaneous (found under the skin) adipose tissue (SAT) is considered protective. Metabolic syndrome spectrum (MetS) is obesity with a range of risk factors involved in other metabolic conditions—including diabetes. The role of VAT and SAT across the MetS remains poorly understood. Using a 6- to 23-year-old nonhuman primate (sex not stated) model for MetS, researchers found that T-cell signaling—specifically T-cell exhaustion—is a major characteristic of poor metabolic health related to both VAT and SAT. These findings provide new insights into the importance of the adaptive immune system—such as T cells—in unhealthy adipose tissue linked to metabolic diseases. Supported by ORIP (P40OD010965, T32OD010957, T35OD010946), NCATS, NCI, NHLBI, and NIAID.
Therapeutic Delivery of Albumin-Binding siRNA Targeting IRS2 to Diverse Cell Types Reduces Mammary Tumor Growth
Tocheny et al., Molecular Therapy. 2026.
https://pubmed.ncbi.nlm.nih.gov/41612694
Aggressive subtypes of breast cancer remain difficult to treat with current therapies. A new type of drug, oligonucleotide (short chains of DNA or RNA) therapies, modifies gene expression in cancer cells, hindering the formation of proteins within the cells that drive cancer progression. Efficient delivery of oligonucleotides, such as small interfering RNAs (siRNAs), remains a challenge for this class of drugs. Researchers chemically modified siRNAs to bind to an albumin-binding dendrimer (molecules that interact with albumin, a transportation protein found in blood). Using female human and mouse cell cultures, researchers identified siRNAs that target IRS2, a signaling protein involved in triple-negative breast cancer (TNBC). Using a 7- to 9‑week-old female mouse model for TNBC, researchers found that the siRNA reduced IRS2 expression in tumor and stromal cells (cells that create connective tissue for structural support). Results also showed that tumor growth was reduced, vascularization (embedding of blood vessels into the tumor) was decreased, and macrophage phenotypes (physical characteristics) were altered. These findings support the use of siRNAs to target different cell populations within breast tumors and to inhibit a key driver of breast cancer. Supported by ORIP (K01OD034451, S10OD020012), NCATS, NCI, and NIGMS.
Rhesus Macaques with an OPA1 Mutation Demonstrate Features of Autosomal Dominant Optic Atrophy
Jaggers et al., PNAS. 2026.
https://pubmed.ncbi.nlm.nih.gov/41984835
Autosomal dominant (a disease that is caused by a single mutated copy of a gene) optic atrophy (ADOA) is an inherited optic nerve disease that causes vision loss. ADOA is caused by mutations in the gene OPA1, and therapies for ADOA are limited. Using a 4-month-old to 29-year-old spontaneous nonhuman primate (NHP) model for ADOA (both sexes used), researchers observed retinal nerve fiber (tissue lining the back of the eye) thinning and abnormal mitochondrial (organelles in cells that produce energy) function in retina cells. The NHP model for ADOA also showed a broad range of phenotypes (physical characteristics) that mimic the clinical variability seen in patients with ADOA. These findings highlight the use of the NHP model for ADOA to test new therapies that may benefit patients. Supported by ORIP (P51OD011107, T35OD010956), NEI, NIA, NIGMS, and NIMH.
Single-Cell Morphodynamical Trajectories Enable Prediction of Gene Expression Accompanying Cell State Change
Copperman et al., Cell Systems. 2026.
https://pubmed.ncbi.nlm.nih.gov/41932341
Extracellular signals (signals from outside the cell) can alter pathways within the cell, which leads to changes in the cell’s phenotype (physical characteristics). The connection between the molecular pathways within the cell that cause phenotypic changes—such as motility and morphology—remains poorly understood. Using female human cell lines isolated from breast disease tissue, researchers captured imaging and transcriptomics (all RNA molecules expressed in a cell) data over time for single cells and developed data-driven models to map connections. The researchers called this approach the molecular and morphodynamics-integrated single-cell trajectories (MMIST). Results showed that MMIST predicted gene expression profiles that were caused by specific extracellular signals and associated with reversable changes in a cell’s phenotype (epithelial-mesenchymal transition and mesenchymal-epithelial transition). The MMIST model provides a foundation for understanding the transition of a cell’s phenotype to develop therapies that inhibit these changes. The model also could be developed further to include more cell phenotypes to extend its use to more tissues and pathological (disease-causing) states. Supported by ORIP (K01OD031811), NCI, and NHGRI.