Biology subjects

Zhang, Q.-Y.

Publications and source records attributed to Zhang, Q.-Y..

12 recordsLinked to original sources

bioRxiv2026

A split-control criterion for few-shot adaptation in single-cell perturbation prediction

Few-shot adaptation can help or harm single-cell perturbation prediction, but conventional evaluation shares a control estimate between calibration responses and held-out targets. We show how methods carry control error into their predictions and derive its contribution to score inflation. Nested control-depth experiments support inverse-depth scaling of inner-product inflation; correlation inflation also depends on the control noise-to-signal ratio. Independent-control scoring changed the rank of 40 of 52 configuration-dataset entries. We introduce SafeDelta, a split-control criterion that uses calibration data to decide whether to adapt. Across six datasets, mean gated gain was non-negative under the original two-control evaluation. On a deep plate, fixed predictions and decisions retained positive mean gains under three additional independent control references. The same reproducibility principle identified a fibrosis programme that localises to scar in human liver. These results inform adaptation decisions and control-depth planning.

bioinformatics↗

bioRxiv2025

Structural Basis of Asymmetric Class C GPCR activation and distinct Gq coupling induced by force stimulation

Mechanosensation is essential for diverse physiological processes. While many G protein-coupled receptors (GPCRs) are known to be mechanosensitive, the underlying mechanism remains largely unknown. Here, we reveal that mechanical force induces Gq activation of mGlu2, a balance modulator residing in kinocilia, but not other 7 mGlu members. Force activates mGlu2 through a conserved N-terminal force transduction motif (FTM) via a unique cis mechanism. We engineered a potent FTM-derived peptide agonist that recapitulates force-induced activation and resolved cryo-EM structures of apo-mGlu2, FTM-mGlu2, LFTM-{Psi}EK-mGlu2 and LFTM-{Psi}EK-mGlu2-Gq. The structures reveal that an atypical FTM binding to a previously uncharacterized pocket induces asymmetric 7TM domain rearrangement, enabling Gq coupling via an ICL1-TM3/6/7 interface, fundamentally distinct from the glutamate-induced Gi coupling mode of mGlu2. Compared with Gi-coupled mGlu2, the 5 helix of Gq rotated by 180{degrees}, penetrating deeper (8 [A]) into a hydrophobic pocket. Disruption of the M7947.32-F7806.57-F7766.53 hydrophobic triad core and a conformational propagation path predominantly comprising TM6-7 residues are identified as key elements mediating force induced mGlu2 activation. Further In vivo rescue experiments support that mGlu2s mechanosensitivity is dependent on FTM and is required for vestibular function. This work establishes a paradigm for class C GPCR mechanotransduction, revealing unprecedented structural mechanisms underlying force-induced Gq coupling and offering a chemical toolset to modulate mechanical signaling of GPCR.

cell biology↗

bioRxiv2025

A Mechanosensitive GPCR at vestibular kinocilium is required for normal balance

Intracellular calcium increase and neurotransmitter release in vestibular hair cells (VHCs) play central roles in equilibrioception, which is one of the basic senses essential for daily life activities and movement in mammals. Independent of mechano-electrical transduction (MET), whether Gq protein-coupled receptor (GqPCR) signaling participate in the regulation of intracellular calcium dynamics and induce neuronal transmitter release in hair cells remains unknown. We screened mechanosensitive GqPCRs in VHCs and found that a Class C GPCR, metabotropic glutamate receptor 2 (mGlu2), is expressed in kinocilia and is essential for normal balance. Notably, the dispensable role of mGlu2 in normal hearing is consistent with absent of mature kinocilia in cochlea hair cells. Different from the conventional mGlu2-Gi signaling, the sensing of mechanical signals by mGlu2 activates the Gq-PLCD4 pathway, increases intracellular calcium concentration and promotes neurotransmitter release in VHCs. Hair cell-specific deficiency of either Grm2 or Gnaq, or knockdown of Plcd4 expression, but not deficiency of another GqPCR Gpr68, causes significant balance deficits. Reintroduction of mGlu2 into the VHCs of Pou4f3-CreER+/- Grm2fl/fl mice restore vestibular functions. Our study reveals a previously uncharacterized role of GPCR signaling in equilibrioception and provides important insight into kinocilia signaling in VHCs, which are absent in mature cochlear hair cells.

cell biology↗

bioRxiv2025

Superficial stromal cell population in the mouse uterus require METTL14 for development and functional competence to support embryo implantation

Uterine stromal cells are critical for pregnancy, coordinating embryo implantation, placental development, and maintenance of gestation. Single-cell RNA-seq analyses have identified two distinct stromal cell populations in the mouse uterus: superficial and deep stromal cells. However, their functional specialization remains unresolved. Here, we show that mice lacking methyltransferase-like 14 (METTL14), a core enzyme of the m6A methyltransferase complex, exhibit a selective depletion of superficial stromal cells while preserving deep stromal cells. This genetic model allowed us to investigate the physiological role of superficial stromal cells in uterine function. Paralleled by the aberrant development and loss of superficial stromal cells, Mettl14 deletion impaired embryo implantation and decidualization. Transcriptomic profiling revealed that Mettl14 deficiency disrupts hormonal signaling by upregulating estrogen (E2)-responsive genes and downregulating progesterone (P4)-responsive genes, resulting in aberrant development and loss of superficial stromal cells. Mechanistically, Mettl14 ablation reduces m6A methylation in the 3'-UTR of Esr1 mRNA, thereby impairing m6A-dependent mRNA degradation and elevating ESR1 expression, which amplifies E2 signaling. This study underscores the essential role of METTL14 in maintaining the superficial stromal cell population required for embryo implantation by regulating Esr1 mRNA stability through m6A modification.

physiology↗

bioRxiv2025

Programmed downregulation of METTL3 is essential for decidualization in both humans and mice

N6-methyladenosine (m6A), the most abundant mRNA modification in eukaryotes, plays an essential role in regulating gene expression. Our prior research, alongside that of others, demonstrated that conditional uterine knockout of methyltransferase-like 3 (METTL3), the enzyme responsible for m6A modification, led to complete failure of embryo implantation and decidualization. Intriguingly, METTL3 expression is downregulated rather than upregulated in human endometrial stromal cells (HESCs) during in vitro decidualization and in mouse decidual tissues during pregnancy. We hypothesized that this decline in METTL3 expression is indispensable for successful decidualization. To test this hypothesis, we overexpressed METTL3 in HESCs and observed impaired decidualization in vitro. Additionally, we generated genetically engineered mice with uterine-specific METTL3 overexpression using Pgr-Cre, which exhibited subfertility mainly due to impaired decidualization. Further investigation revealed a marked decrease in HAND2, a well-established regulator of decidualization, following METTL3 overexpression. Mechanistically, we uncovered that METTL3 destabilizes HAND2 mRNA via m6A modification at the 5'-UTR. In summary, our study underscores the critical role of programmed METTL3 downregulation in decidualization by sustaining HAND2 expression.

physiology↗

bioRxiv2025

CTCF is crucial for decidualization of uterine stromal cells through facilitating HOXA11 expression

CCCTC-binding factor (CTCF), a highly versatile transcriptional regulator and chromatin architectural protein, plays a pivotal role in mammalian development. In this study, we investigated the function of CTCF in uterine biology during pregnancy. We observed that CTCF expression in the human endometrium decreases from the proliferative to the secretory phase of the menstrual cycle. Similarly, in cultured human endometrial stromal cells (hESCs), CTCF expression declines during in vitro decidualization. Using siRNA-mediated knockdown, we demonstrated that CTCF is essential for the early phase of decidualization but dispensable in later stages. Notably, CTCF depletion reduces the expression of HOXA11, a well-established regulator of decidualization, and overexpression of HOXA11 rescues the decidualization defects caused by CTCF loss, identifying HOXA11 as a key downstream effector of CTCF. Mechanistically, CTCF binds to the HOXA11 promoter to facilitate its transcriptional activation. Furthermore, uterine-specific knockout of CTCF in Pgr-Cre mice leads to female infertility, characterized by diminished HOXA11 expression, impaired uterine receptivity, and defective decidualization. Collectively, our findings highlight the critical role of the CTCF-HOXA11 axis in decidualization in both humans and mice, providing novel insights into the molecular regulation of this process and potential therapeutic targets for reproductive disorders.

physiology↗

bioRxiv2025

NAT10 governs uterine function and fertility by stabilizing progesterone receptor mRNA via ac4C modification

The N4-acetylcytidine (ac4C) modification is one of the most abundant chemical modifications in mammalian transcriptome, which plays a crucial role in regulating gene expression across various biological processes. In this study, we investigate the role of N4-acetyltransferase 10 (NAT10), the sole enzyme responsible for catalyzing the ac4C modification, in uterine function. Our findings revealed that knockdown of NAT10 in cultured human endometrial stromal cells leads to decreased progesterone receptor (PGR) expression and compromised decidualization. Mechanistically, NAT10 is found to enhance the stability of PGR mRNA through its ac4C modification in the coding sequence (CDS). Furthermore, conditional deletion of Nat10 in the mouse uterus using Pgr-Cre resulted in defective pubertal uterine development, characterized by a thinner stroma and reduced endometrial gland number. These mice were infertile in adulthood, experiencing failures in both implantation and decidualization. However, heterozygous Nat10 conditional knockout mice showed reduced NAT10 expression in the uterus without affecting uterine development or fertility. To bridge the gap between heterozygous and homozygous knockout conditions, we employed Remodelin, an inhibitor of NAT10, in adult female mice, to mimic an intermediate gene dosage. Our results demonstrated that inhibiting NAT10 with Remodelin preserved uterine structures but disrupted the PGR signaling pathway, leading to impaired uterine function during pregnancy. In conclusion, our study provides compelling evidence that NAT10 safeguards uterine function and fertility by regulating the ac4C modification of PGR mRNA. SignificanceHere we identified NAT10-catalyzed ac4C modification of progesterone receptor (PGR) mRNA as a crucial mechanism regulating PGR expression by enhancing its mRNA stability. In vitro studies using human endometrial stromal cells show that the NAT10-PGR axis is required for decidualization. Additionally, genetic and pharmacologic manipulations in mice further demonstrate the necessity of NAT10-dependent P4/PGR signaling for uterine function during implantation and decidualization. Our findings highlight the importance of NAT10-mediated ac4C modification in maintaining PGR expression and uterine function.

physiology↗

bioRxiv2023

PCMD: A Multilevel Comparison Database of Intra- and Cross-species Metabolic Profiling in 530 Plant Species

Comparative metabolomics plays a crucial role in understanding gene function, exploring metabolite evolution, and improving crop genetic breeding. However, a systematic platform for comparing intra- and cross-species metabolites is currently lacking. In this study, we present the plant comparative metabolome database (PCMD; http://yanglab.hzau.edu.cn/PCMD), a comprehensive multi-level comparison database encompassing intra- and cross-species metabolic profiling in 530 plants. Remarkably, PCMD offers a multi-level platform for comparative metabolite analysis, allowing for the examination of metabolite characteristics across species at various levels including species, metabolites, pathways, and biological taxonomy. In addition, PCMD standardizes metabolite numbering, establishing a uniform system based on existing metabolite-related databases. The database also provides a range of user-friendly online tools, such as Species-comparison, Metabolites-enrichment, and ID conversion, enabling users to perform comparisons and enrichment analyses of metabolites across different species. PCMD stands out as the most comprehensive and species-rich comparative plant metabolomics database currently available, as demonstrated by two case studies that highlight its ability to supplement phylogenetic similarity mining among species through phylogenetic trees and offer new insights into the diversity and species-specificity of metabolites.

bioinformatics↗

bioRxiv2023

Force-sensing LPHN2 is indispensable for normal hearing and mediates MET in cochleae through Gs and CNGA3 coupling

The conversion of force sensation into electrical signals via mechanoelectrical transduction (MET) is considered the key step in auditory perception. Here, we found that G protein-coupled receptor (GPCR) LPHN2/ADGRL2 was expressed at the tips of stereocilia in cochlear hair cells and was associated with MET channel components. Hair cell-specific LPHN2 deficiency caused hearing loss and impaired MET responses. A specific inhibitor of LPHN2, developed by in silico screening and pharmacological characterization, reversibly blocked the MET response. Mechanistically, administration of force to LPHN2 activated TMC1 through direct interaction and caused conformational changes in TMC1 in vitro. Furthermore, the sensing of force by LPHN2 stimulated Ca2+ responses and neurotransmitter release in hair cells. Finally, hearing loss in LPHN2-deficient mice was reversed by the re-expression of LPHN2-GAIN in cochlear hair cells. The important roles of LPHN2 in auditory perception and a TMC-coupled force sensor indicated that GPCRs could be candidate auditory receptors.

physiology↗

bioRxiv2020

Aglycone polyether ionophores as broad-spectrum agents inhibit multiple enveloped viruses including SARS-CoV-2 in vitro and successfully cure JEV infected mice

Infections with zoonotic viruses, such as flaviviruses, influenza virus, and the SARS-CoV-2 pandemic coronavirus constitute an increasing global risk. Hence, an urgent need exists for the development of broad-spectrum antivirals to prevent such outbreaks. Here, we show that the maduramycin and CP-80,219 aglycone polyether ionophores exhibit effective broad-spectrum antiviral activity, against various viruses, including Japanese encephalitis virus (JEV), Dengue virus (DENV), Zika virus (ZIKV), and Chikungunya virus (CHIKV), while also exhibiting promising activity against PR8 influenza virus and SARS-CoV-2. Moreover, liposome-encapsulated maduramycin and CP-80,219 provide full protection for mice from infection with JEV in vivo. Mechanistic studies suggest that aglycone polyether ionophores primarily inhibit the viral replication step without blocking endosome acidification to promote the fusion between viral and cellular membranes. The successful application of liposomes containing aglycone polyether ionophores in JEV-infected mice offers hope to the development of broad-spectrum antiviral drugs like penicillin back to 1940s.

microbiology↗

bioRxiv2019

BTB-TAZ domain protein MdBT2 modulates malate accumulation by targeting a bHLH transcription factor for degradation in response to nitrate

Excessive application of nitrate, an essential macronutrient and a signal regulating diverse physiological processes, decreases malate accumulation in apple fruit, but the underlying mechanism remains poorly understood. Here, we show that an apple BTB/TAZ protein MdBT2 is involved in regulating malate accumulation and vacuolar pH in response to nitrate. In vitro and in vivo assays indicate that MdBT2 interacts directly with and ubiquitinates a bHLH transcription factor, MdCIbHLH1, via the ubiquitin/26S proteasome pathway in response to nitrate. This ubiquitination results in the degradation of MdCIbHLH1 protein and reduces the transcription of MdCIbHLH1-targeted genes involved in malate accumulation and vacuolar acidification including MdVHA-A encoding a vacuolar H+-ATPase gene, and MdVHP1 encoding a vacuolar H+-pyrophosphatase gene, as well as MdALMT9 encoding a aluminum-activated malate transporter gene. A series of transgenic analyses in apple materials including fruits, plantlets and calli demonstrate that MdBT2 controls nitrate-mediated malate accumulation and vacuolar pH at least partially, if not completely, via regulating the MdCIbHLH1 protein level. Taken together, these findings reveal that MdBT2 regulates the stability of MdCIbHLH1 via ubiquitination in response to nitrate, which in succession transcriptionally reduces the expression of malate-associated genes, thereby controlling malate accumulation and vacuolar acidification in apples under high nitrate supply.

molecular biology↗

bioRxiv2019

Epitranscriptomic regulation of the response to the air pollutant naphthalene in mouse lungs: from the perspectives of specialized translation and tolerance linked to the writer ALKBH8

BackgroundThe epitranscriptomic writer Alkylation Repair Homolog 8 (ALKBH8) is a tRNA methyltransferase that modifies the wobble uridine of selenocysteine tRNA to promote the specialized translation, via stop codon recoding, of proteins that contain selenocysteine. Corresponding selenoproteins play critical roles in protecting against reactive oxygen species and environmental stress. Using a novel animal model deficient in Alkbh8, we have investigated the importance of epitranscriptomic systems in the response to naphthalene (NA), an abundant polycyclic aromatic hydrocarbon, glutathione depleter and lung toxicant found in tobacco smoke, gasoline and mothballs.\n\nObjectivesOur goal was to define the molecular reprogramming of Alkbh8 deficient (Alkbh8def) mice and evaluate the roles that the epitranscriptomic writer ALKBH8 and selenoproteins play in mitigating NA-induced toxicity and lung dysfunction.\n\nMethodsWe performed basal lung analysis and NA exposure studies using WT, Alkbh8def and Cyp2abfgs-null mice, the latter of which lack the cytochrome P450 enzymes required for NA bioactivation. We characterized gene expression, molecular markers of damage, viability and tolerance to NA.\n\nResultsUnder basal conditions, lungs from Alkbh8def mice have increased oxidation-reduction potential (ORP) and 8-isoprostane levels, and have reprogrammed at the molecular level to display increased stress response transcripts. In addition, the ALKBH8 writer deficient lungs have a decreased GSH/GSSG ratio. Alkbh8def mice are more sensitive to NA than WT, showing higher susceptibility to lung damage both at the cellular and molecular levels. WT mice develop a tolerance to NA after 3 days, defined as resistance to a high challenging dose after repeated exposures, which is absent in Alkbh8def mice, with writer deficient not surviving NA exposure.\n\nDiscussionWe conclude that the epitranscriptomic writer ALKBH8 plays a protective role against NA-induced lung dysfunction and promotes NA tolerance. Our work provides an early example of how epitranscriptomic systems can regulate the response to environmental stress in vivo.

molecular biology↗