Biology subjects

Cheng, Y.-T.

Publications and source records attributed to Cheng, Y.-T..

10 recordsLinked to original sources

bioRxiv2026

Evolutionarily Conserved Decline of tRNA Mannosyl-Queuosine Links Translational Regulation to Aging and Is Reversed by Queuine

Aging arises from interconnected molecular defects, yet upstream regulatory mechanisms that coordinate these hallmarks remain incompletely defined. While epitranscriptomic regulation has emerged as a critical layer of gene control, the contribution of tRNA-specific modifications to aging remains largely unexplored. Here, we systematically profile tRNA modifications across multiple organs, species, and senescence models and identify mannosyl-queuosine (manQ), a wobble-position modification of tRNAAsp, as the first tRNA-specific modification that consistently declines with age. ManQ depletion is evolutionarily conserved and tightly correlates with functional deterioration. Mechanistically, loss of manQ impairs translational fidelity, leading to proteome imbalance, collapse of proteostasis, and aberrant expression of senescence-associated proteins, including GPNMB. These translational defects intersect with established aging hallmarks and accelerate cellular and organismal aging. We further demonstrate that circulating queuine, a microbiota-derived precursor required for manQ biosynthesis, declines with age in rodents and humans. Queuine deficiency promotes senescence, whereas supplementation restores manQ levels, improves translational accuracy, suppresses p16/p21-driven senescence programs, and re-establishes proteostatic balance. Across species, queuine supplementation extends lifespan and enhances healthspan. In Drosophila, it increases median lifespan by 47% and improves stress resistance and memory. In naturally aging mice, long-term oral administration extends lifespan by 15.3%, reduces DNA methylation age, improves cognitive and motor performance, strengthens antioxidant defenses, remodels the gut microbiota, and alleviates inflammation and metabolic dysfunction without detectable toxicity. Collectively, these findings establish tRNA epitranscriptomic remodeling as a previously unrecognized layer of aging regulation and identify restoration of manQ through queuine supplementation as a multi-system strategy to delay aging.

pharmacology and toxicology↗

bioRxiv2026

Colitis-induced visceral pain recruits central neurotensin neurons that modulate colonic sensitivity

Inflammatory bowel disease produces debilitating visceral pain that remains a major clinical challenge. Notably, many patients experience persistent pain even after the inflammation resolves, indicating a sustained sensitization of central neural circuits that drives enduring pain. The brainstem parabrachial nucleus integrates interoceptive signals from the gastrointestinal tract to elicit both pain perception and affective responses. Using activity-dependent mapping and an RNAscope assay, we identified a neurotensin (NT)-expressing neuronal population in the lateral PBN (PBNL) that is selectively activated during dextran sulfate sodium-induced colitis. In vivo neural activity recordings demonstrate that PBNL NT neurons encode colon-derived nociceptive signals in an intensity-dependent manner. Silencing these neurons attenuates colonic reflexes evoked by luminal distension and normalizes aberrant gastrointestinal transit and nociceptive licking behavior in colitic mice. Pharmacological blockade of NT signaling alleviates colitis-associated hypersensitivity. These findings identify a central neural population that encodes visceral inflammation and regulates peripheral organ function, and pinpoints neurotensin as a promising therapeutic target to treat colitis-induced visceral pain.

neuroscience↗

bioRxiv2025

Targeted intervention of senescence induced by a 5' half fragment of tRNASec(NCA) with antisense oligonucleotide extends healthspan and lifespan in mice

In light of increasing attention being paid to aging research globally, the accumulation of aging hallmarks and their corresponding targeting therapeutics have been substantially revealed. However, uncovering the genuine drivers within epigenetic alterations that lead to aging remains a formidable challenge. In this study, we identified tRNASec(NCA) as the most severely damaged tRNA species in the kidneys of naturally aged mice. This damage not only dysregulated selenoproteins with anti-aging effects, but also generates a 5'-tRNA fragment cleaved at the 34th position, which accumulates in an age-dependent manner. Mechanistically, the 5'-tRNASec(NCA) half interacts and activates Toll-like receptor 7, thereby triggering innate immune responses and promoting cellular senescence in both mice and human cells. Moreover, in a naturally aged mice model, administration of an antisense oligonucleotide (ASO) targeting the 5'-tRNASec(NCA) half remarkably ameliorates aging markers, enhances telomere length, and extends healthspan and lifespan. In addition, ASO-5'-tRNASec(NCA) half plays another role in directly targeting and downregulating BCAT1 via the RNAi pathway to intervene in the senescence process. Our findings underscore tRNA damage as a novel aging hallmark, and targeting the damage-induced products presents a novel strategy for aging intervention, thus expanding our knowledge of the aging process.

genetics↗

bioRxiv2025

Lipid nanoparticle delivery of siRNA to dorsal root ganglion neurons to treat pain

Sensory neurons within the dorsal root ganglion (DRG) are the primary trigger of pain, relaying activity about noxious stimuli from the periphery to the central nervous system; however, targeting DRG neurons for pain management has remained a clinical challenge. Here, we demonstrate the use of lipid nanoparticles (LNPs) for effective intrathecal delivery of small interfering RNA (siRNA) to DRG neurons, achieving potent silencing of the transient receptor potential vanilloid 1 (TRPV1) ion channel that is predominantly expressed in nociceptor sensory neurons. This leads to a reversible interruption of heat-, capsaicin-, and inflammation-induced nociceptive conduction, as observed by behavioral outputs. Our work provides a proof-of-concept for intrathecal siRNA therapy as a novel and selective analgesic modality.

neuroscience↗

bioRxiv2024

Comparative spatiotemporal single cell transcriptomes reveal rewiring of pre-existing regulations during emergence of Kranz anatomy in C4 grasses

Many of the worlds most productive food and bioenergy crops use C4 photosynthesis, which have high photosynthetic efficiency due to a Kranz anatomy-based CO2 concentrating mechanism. Here, we took a comparative transcriptomics approach using single cell spatial transcriptomes of leaf primordia for maize (Zea mays) and single cell RNA-seq (scRNA-seq) atlases of corresponding leaf tissues for three C4 species (Zea mays, Sorghum bicolor, Setaria viridis) and one C3 rice (Oryza sativa) to study regulatory networks involved in the development and evolution of Kranz anatomy. We show that the formation of Kranz anatomy involves extensive recruitment and modification of pre-existing regulatory modules, especially the SHR-SCR module and the auxin signaling pathway. Members of the INDETERMINATE DOMAIN (IDD) family transcription factors, including IDD7 and IDDP1, contribute to the modification of the involved modules. These extensive recruitment and modification of existing genetic regulatory programs underlie the repeated emergence of C4 photosynthesis during evolution.

plant biology↗

bioRxiv2024

Three-photon excited fluorescence microscopy enables imaging of blood flow, neural structure and inflammatory response deep into mouse spinal cord in vivo

Nonlinear optical microscopy enables non-invasive imaging in scattering samples with cellular resolution. The spinal cord connects the brain with the periphery and governs fundamental behaviors such as locomotion and somatosensation. Because of dense myelination on the dorsal surface, imaging to the spinal grey matter is challenging, even with two-photon microscopy. Here we show that three-photon excited fluorescence (3PEF) microscopy enables multicolor imaging at depths of up to ~550 m into the mouse spinal cord, in vivo. We quantified blood flow across vessel types along the spinal vascular network. We then followed the response of neurites and microglia after occlusion of a surface venule, where we observed depth-dependent structural changes in neurites and interactions of perivascular microglia with vessel branches upstream from the clot. This work establishes that 3PEF imaging enables studies of functional dynamics and cell type interactions in the top 550 m of the murine spinal cord, in vivo.

neuroscience↗

bioRxiv2023

Remote neuronal activity drives glioma infiltration via Sema4f

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform to examine GBM infiltration, we identified an activity dependent infiltrating population present at the leading edge of mouse and human tumors that is enriched for axon guidance genes. High-throughput, in vivo screening of these genes identified Sema4F as a key regulator of tumorigenesis and activity-dependent infiltration. Furthermore, Sema4F promotes the activity-dependent infiltrating population and propagates bi-directional signaling with neurons by remodeling tumor adjacent synapses towards brain network hyperactivity. Collectively, our studies demonstrate that subsets of neurons in locations remote to primary GBM promote malignant progression, while revealing new mechanisms of tumor infiltration that are regulated by neuronal activity.

cancer biology↗

bioRxiv2023

Inhibitory input directs astrocyte morphogenesis through glial GABABR

Communication between neurons and glia plays an important role in establishing and maintaining higher order brain function. Astrocytes are endowed with complex morphologies which places their peripheral processes in close proximity to neuronal synapses and directly contributes to their regulation of brain circuits. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unknown. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABABR and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABABR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together our studies identify input from inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes.

neuroscience↗

bioRxiv2023

Activity-dependent induction of astrocytic Slc22a3 regulates sensory processing through histone serotonylation

Neuronal activity drives global alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. Here we show that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduces serotonin levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduces expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study reveals that neuronal activity orchestrates transcriptional and epigenomic responses in astrocytes, while illustrating new mechanisms for how astrocytes process neuromodulatory input to gate neurotransmitter release for sensory processing.

neuroscience↗

bioRxiv2021

Mindfulness Training Alters Resting-State EEG Dynamics in Novice Practitioners via Mindful Breathing and Body-scan

Mindfulness-based stress reduction (MBSR) has been proven to improve mental health and quality of life. This study examined how mindfulness training and various types of mindfulness practices altered brain activity. Specifically, the spectral powers of scalp electroencephalography (EEG) of the MBSR group who underwent an 8-week mindfulness training--including mindful breathing and body-scan--were evaluated and compared with those of the waitlist controls. Empirical results indicated that the long-term mindfulness intervention effect significantly elevated the resting-state beta powers and reduced resting-state delta powers in both practices; such changes were not observed in the waitlist control. Compared with mindful breathing, body-scanning resulted in an overall decline in EEG spectral powers at both delta and gamma bands among trained participants. Together with our preliminary data of expert mediators, the aforementioned spectral changes were salient after intervention, but mitigated along with expertise. Additionally, after receiving training, the MBSR groups mindfulness and emotion regulation levels improved significantly, which were correlated with the EEG spectral changes in the theta, alpha, and low-beta bands. This study elaborated the neurophysiological correlates of mindfulness practices, suggesting that MBSR might function as a unique internal processing that involves increased vigilant capability and induces alterations similar to other cognitive training.

neuroscience↗