Biology subjects

Weng, Y.-L.

Publications and source records attributed to Weng, Y.-L..

4 recordsLinked to original sources

bioRxiv2026

Loss of m6A unmasks a senescence-associated inflammatory program in human microglia

Chronic microglial inflammation and cellular senescence are hallmarks of the aging brain, yet the molecular events that lock microglia into durable inflammatory states remain poorly understood. Prior studies using genetic manipulation of METTL3 have implicated the RNA modification N6-methyladenosine (m6A) in senescence. However, because METTL3 also has m6A-independent functions, loss-of-function approaches cannot distinguish whether senescence arises from reduced m6A itself or from broader disruption of METTL3-dependent pathways. This question is further complicated in microglia, where METTL3 has been reported to promote acute inflammatory activation, suggesting that m6A may have context-dependent effects on immune state. Whether sustained reduction of m6A is sufficient to drive microglial senescence has therefore remained unresolved. Here, we show that selective catalytic inhibition of METTL3 with STM2457 lowers global m6A and is sufficient to induce a senescence-like inflammatory state in human HMC3 microglia. This state includes increased senescence-associated {beta}-galactosidase activity, elongated cellular morphology, reduced proliferation, Lamin B1 loss, and remodeling of nuclear architecture. Transcriptomic profiling revealed suppression of mitotic gene programs together with a SASP-like inflammatory output marked by NF-{kappa}B and interferon signatures. Rather than causing broad transposable-element derepression, m6A inhibition promoted cytoplasmic double-stranded RNA accumulation and a selective HERVK-associated response. These findings support a model in which m6A helps preserve microglial homeostasis by limiting immunogenic RNA accumulation and senescence-associated inflammatory remodeling. Together, our study identifies m6A as a safeguard against microglial senescence and suggests that reduced m6A-dependent RNA regulation may contribute to chronic inflammatory remodeling in the aging brain.

neuroscience↗

bioRxiv2025

Biochemical Profiling and Structural Basis of ADAR1-Mediated RNA Editing

ADAR1 is a pivotal regulator in RNA-induced immune responses by catalyzing the conversion of adenosine to inosine on double-stranded RNA. Mutations on ADAR1 are associated with human autoimmune disease, and targeting ADAR1 has been proposed for cancer immunotherapy. However, the molecular mechanisms governing ADAR1-mediated RNA editing remain enigmatic. Here, we provide detailed biochemical and structural characterizations of human ADAR1. Our biochemical profiling reveals that ADAR1 editing is both sequence and RNA duplex length-dependent, but can well tolerate mismatches near the editing site. Moreover, our high-resolution structures of ADAR1-RNA complexes, coupled with mutagenesis studies, revealed the molecular basis for RNA binding, substrate selection, dimerization, and the crucial role of the RNA-binding domain 3 for ADAR1 editing. The ADAR1 structures also help explain the potential defects of disease-associated mutations, where biochemical and RNA-sequencing analysis further indicate some of the mutations preferentially impact the editing of RNAs with short duplex. Our findings illustrate the molecular mechanism of ADAR1 editing and provide clues for deciphering its role in immune regulation and drug targeting. HIGHLIGHTSO_LIBiochemical profiling of ADAR1 RNA substrate preference C_LIO_LIAtomic resolution structures of ADAR1 with two physiological RNA substrates C_LIO_LIDisease-related mutations of ADAR1 preferentially impact RNA editing with short dsRNA. C_LIO_LIRNA-binding domain 3 is essential for ADAR1 RNA capture and editing C_LI

biochemistry↗

bioRxiv2024

Deficiency of m6A RNA methylation promotes ZBP1-mediated cell death

m6A RNA methylation suppresses the immunostimulatory potential of endogenous RNA. Deficiency of m6A provokes inflammatory responses and cell death, but the underlying mechanisms remain elusive. Here we showed that the noncoding RNA 7SK gains immunostimulatory potential upon m6A depletion and subsequently activates the RIG-I/MAVS axis to spark interferon (IFN) signaling cascades. Concomitant excess of IFN and m6A deficiency synergistically facilitate the formation of RNA G-quadruplexes (rG4) to promote ZBP1-mediated necroptotic cell death. Collectively, our findings delineate a hitherto uncharacterized mechanism that links m6A dysregulation with ZBP1 activity in triggering inflammatory cell death.

molecular biology↗

bioRxiv2019

Knocking out non-muscle myosin II in retinal ganglion cells promotes long-distance optic nerve regeneration

In addition to altered gene expression, pathological cytoskeletal dynamics in the axon are another key intrinsic barrier for axon regeneration in the central nervous system (CNS). Here we showed that knocking out myosin IIA/B in retinal ganglion cells alone either before or after optic nerve crush induced marked and sustained optic nerve regeneration. Combined Lin28 overexpression and myosin IIA/B knockout led to synergistic promoting effect and long-distance axon regeneration. Immunostaining, RNA-seq and western blot analyses revealed that myosin II deletion did not affect known axon regeneration signaling pathways or the expression of regeneration associated genes. Instead, it abolished the retraction bulb formation and significantly enhanced the axon extension efficiency. The study provided clear evidence that directly targeting neuronal cytoskeleton was sufficient to induce strong CNS axon regeneration, and combining gene expression in the soma and modified cytoskeletal dynamics in the axon was a promising approach for long-distance CNS axon regeneration.

neuroscience↗