Biology subjects

Bai, Y.

Publications and source records attributed to Bai, Y..

At least 37 records · Page 2Linked to original sources

bioRxiv2026

Homeobox transcription factor MSX2 down-regulates ERα action to facilitate anti-estrogensensitivity in ERα+ breast cancer

Breast cancer is the most common malignancy among women worldwide. Estrogen receptor (ER)-positive breast cancer is about 70% in the total breast cancer. It has variable prognosis and high recurrent risk, frequently developing resistance to endocrine therapies. Herein, we have identified that a homeobox transcription factor MSX2 downregulated in ER-positive breast cancer is correlated with the advanced grade and poor survival outcomes. Our results have demonstrated that MSX2 interacts with ER to inhibit ER-mediated transactivation. Mechanistically, MSX2 associates with HDAC1/HDAC2 to form a protein complex. MSX2 is required for recruitment of HDAC1/HDAC2 complex to estrogen response elements (EREs) region on ER downstream target genes, reducing histone H3K9ac and H3K27ac levels to inactivate gene transcription. Functionally, ectopic expression of MSX2 suppresses cell growth and enhances the sensitivity to anti-estrogen treatment in ER-positive breast cancer cells. Our results indicate that MSX2 as a novel co-repressor of ER is involved in suppression of ER-positive breast cancer progression. Restoring MSX2 protein may provide a promising strategy to overcome endocrine resistance in ER-positive breast cancer.

Molecular Biology↗

bioRxiv2026

Lineage Memory and Convergent Adaptation Dictate the Single-Cell and Spatial Architecture of Brain Malignancies

How diverse cancer lineages navigate the draconian central nervous system environment--whether constrained by ancestral ontogeny or driven by convergent adaptation--remains a fundamental biological paradox. To decode this, we integrated extensive in-house and public resources to construct the largest single-cell atlas of primary and secondary brain malignancies (>550,000 cells). We demonstrate that malignant cells balance strict lineage imprinting with shared brain-adaptive programs, powerfully converging upon a dominant pan-cancer mesenchymal (MES)-like state alongside a SYT1+ pioneer subpopulation exploiting neuronal mimicry. Concurrently, the microenvironment undergoes lineage-constrained divergence. The myeloid landscape shifts from a resident-dominated architecture in gliomas to extensive blood-borne infiltration in metastases. Lymphoid responses parallel this, crowning laryngocarcinoma as an ultra-hot subtype and revealing that massive T cell influx in highly infiltrated niches is paradoxically driven into terminal exhaustion, contrasting with severe immune exclusion in cold tumors. Furthermore, stromal-vascular adaptation couples pro-angiogenic tip-endothelial activation with a dynamic opposition between structural extracellular matrix (ECM) deposition and focal proteolytic degradation. Anchored by the pan-cancer MES adaptation, we leveraged subcellular spatial transcriptomics to redefine the microenvironment around four MES-like architectural niches, mapping an evolutionary trajectory from perivascular entry to immunosuppressive stromal remodeling. Finally, projecting these architectures onto independent clinical cohort establishes the MES-S2 proliferative niche as the primary driver of severe clinical deterioration across both transcriptomic and proteomic dimensions.

Cancer Biology↗

bioRxiv2026

Dehydration/1,6-addition-based Site-specific Bioconjugation Unveils Norepinephrinylation as a Widespread Post-translational Modification in the Cellular Proteome

Norepinephrine (NE) is a key neurotransmitter and hormone involved in diverse physiological and pathological processes. Beyond its canonical non-covalent signaling through binding adrenergic receptors, NE also induces protein post-translational modifications (PTMs), representing an emerging regulatory mechanism. Two major forms of NE-derived PTMs have been proposed: non-enzymatic norepinephrinylation (NEylation) of cysteine residues mediated by NE quinone and transglutaminase 2 (TG2)-catalyzed NEylation of glutamine residues. However, the cellular abundance, biochemical basis, and pathophysiological roles of NEylation remain poorly understood due to limited detection tools. Here, we report a novel bioconjugation chemistry for selective labeling and enrichment of the endogenous NEylation proteome in cell lines and tissues, which is based on acid-catalyzed dehydration and 1,6-addition to thiol probes. This strategy enables fluorescence imaging and chemical proteomic profiling, revealing NEylation as a widespread PTM that affects enzymatic activities of modified proteins, including protein tyrosine-protein phosphatase non-receptor type 11 (PTPN11). Visual Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/731782v3_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@406ac5org.highwire.dtl.DTLVardef@121d6b9org.highwire.dtl.DTLVardef@98354corg.highwire.dtl.DTLVardef@d312ef_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2026

Outbred Drosophila populations reveal diet-dependent genetic effects on development time

Metabolic effects of genetic variation often depend on diet, yet the loci underlying diet-dependent developmental responses remain incompletely defined. Here we combine multi-trait phenotyping of Drosophila Genetic Reference Panel lines with genome-wide mapping in newly developed Drosophila Recombinant Populations. High sugar causes genotype- and life-stage-dependent changes in metabolic and life-history traits, with development time emerging as a highly heritable, sugar-sensitive phenotype. Mapping in 16 outbred advanced intercross populations reveals distinct association landscapes under low- and high-sugar diets, with a concentrated low-sugar signal, a more distributed high-sugar pattern, and identified genotype-by-diet loci including tap, Eip75B and Cerk. Functional perturbation supports diet-dependent effects for several prioritized candidates. Allele-frequency analyses identify operationally defined thrifty-like variants associated with delayed development under high sugar and relatively earlier development under low sugar; these variants are enriched for cell-adhesion, neurodevelopmental, and morphogenetic processes. Together, these results establish an outbred Drosophila framework for dissecting how dietary sugar remodels the genetic architecture of development time.

genetics↗

bioRxiv2026

Decoding Immune Reconstitution Failure in People Living with HIV through Single-cell Genomics

Immune non-responders (INRs), a subset of people living with HIV (PLWH), fail to achieve full immune reconstitution and remain at increased risk of morbidity, mortality, and non-AIDS-related illnesses. As the mechanisms underlying this impaired immune recovery remain poorly understood, we performed single-cell multi-omics profiling on peripheral blood mononuclear cells from 43 INRs, 47 immune responders and 53 healthy donors. Our dataset comprises 2,744,009 transcriptomes and 1,226,658 chromatin-accessibility profiles across 58 identified immune cell types. INRs exhibited markedly elevated inflammatory signaling, increased apoptotic activity, and dysregulation of immune-activating ligand-receptor interactions. Additionally, we identified 2,996 interaction cis-eGenes and 5,938 cis-caPeaks, and validated key cell type-specific cis-xQTL effects associated with immune reconstitution failure. Furthermore, we identified 3,551 sc-eQTLs and 872 cell-state interaction eQTLs (ieQTLs) in CD4+ T cells. A genotype-specific upregulation of OAS3 in INRs, likely regulated by STAT1, was identified based on these results. We developed scPRISM (single cell Predictive Reconstitution Immune Status Model), a multi-modal framework that integrates scRNA-seq and scATAC-seq data to perform the dual tasks of differentiating disease states and predicting gene expression from chromatin accessibility, thereby deciphering the cell type-specific cis-regulatory basis of the disease. Our study delineates the transcriptional and epigenomic landscape of immune dysregulation in INRs and provides new genetic insights into HIV-associated immune reconstitution failure. These findings offer a foundation for developing biomarkers and precision therapies to restore immune function in PLWH.

genetics↗

bioRxiv2026

Integrative Single-Cell and Multi-Cohort Analysis of the Netrin-1 Signaling Pathway Reveals Divergent Prognostic Trends and Sex-Dimorphic Associations in Glioblastoma

BackgroundThe Netrin-1 dependence receptor pathway plays critical roles in neural development, but its expression landscape and prognostic significance in glioblastoma (GBM) remain poorly characterized. MethodsSingle-cell RNA-seq data from 148,019 cells across 34 tumors (Neftel et al., 2019) were analyzed to map Netrin-1 pathway gene expression across GBM cellular states. Differential gene expression and pathway enrichment analyses were performed on NEO1-defined subpopulations. Bulk RNA-seq survival analysis was conducted across three independent GBM cohorts TCGA (n=106), CGGA mRNAseq_325 (n=137), and CGGA mRNAseq_693 (n=237), totaling 480 patients. Primary analysis used continuous Cox regression (per-SD hazard ratios); meta-analysis employed fixed-effects inverse-variance weighting. ResultsIn GBM single-cell data, Netrin-1 pathway genes showed state-specific enrichment --NEO1, DCC, NTN1, and RGMB were predominantly expressed in oligodendrocyte-precursor (OPC) and neural-progenitor (NPC) states. Cells positive for NEO1 were enriched for neural differentiation programs (nervous system development, p=9.6x10-; Axon Guidance, p=2.8x10-), whereas NEO1-negative cells were dominated by ribosomal/translational and immune activation programs. In the 3-cohort survival meta-analysis, NTN1 (Netrin-1 ligand) emerged as the sole gene reaching meta-analytic significance as a risk factor (Meta HR=1.163 per SD, 95% CI 1.056-1.281, p=0.0021, I{superscript 2}=0%, 3/3 cohorts concordant), while DCC and RGMB showed directionally consistent protective trends (DCC: Meta HR=0.938, 95% CI 0.858-1.025, p=0.156; RGMB: Meta HR=0.979, 95% CI 0.881-1.087, p=0.686; both 3/3 cohorts concordant). NEO1 itself did not independently predict survival (Meta HR=1.008, 95% CI 0.885-1.147, p=0.910). After Bonferroni correction for 10 genes tested (threshold p<0.005), only NTN1 met strict significance. In exploratory sex-stratified analysis of a single cohort (CGGA 693, n=237), NEO1 and NTN1 exhibited female-specific risk enhancement (NEO1: HR=1.417, p=0.014; NTN1: HR=1.249, p=0.019), with minimal effects in males. UNC5B showed context-dependent risk in MGMT-unmethylated tumors (HR=1.331, p=0.037). These sex-dimorphic findings require independent validation. ConclusionsThe Netrin-1 pathway exhibits divergent prognostic trends in GBM, with NTN1 as a risk factor and DCC trending toward protection--consistent with the dependence receptor model. These findings, which should be interpreted as hypothesis-generating, nominate NTN1 as a candidate therapeutic target and highlight the potential importance of sex-stratified evaluation in future Netrin-1-directed trials. Independent replication in larger cohorts is warranted.

cancer biology↗

bioRxiv2026

NFIC-mediated CaSR endocytosis defines a hyperactive TOMM20highCHGAhigh oxyphil cell state as a pathological driver of autonomous secondary hyperparathyroidism

Secondary hyperparathyroidism (SHPT) is a debilitating complication of chronic kidney disease. Its clinical management is frequently compromised by calcimimetic resistance, a refractory state primarily driven by the progressive downregulation of the membrane calcium-sensing receptor (CaSR). Despite the centrality of CaSR as a therapeutic target, the mechanisms governing its aberrant expression and membrane localization remain incompletely elucidated. Here, we generated a single-cell transcriptomic atlas of human parathyroid tissues from SHPT and primary hyperparathyroidism (PHPT) patients, uncovering a unique stromal-immune niche that is specifically induced by uremic stress in SHPT. Our data also observed a striking dissociation between CaSR mRNA and its abundance as a membrane protein in SHPT tissues. Pseudotime trajectory analysis showed a progressive decline in CaSR pathway activity and a concomitant increase in endo-lysosomal activity along the trajectory, terminating in pathological oxyphil cells as the endpoint of chief cell differentiation in SHPT. Mechanistically, Nuclear Factor I C (NFIC) transcriptionally activated clathrin light chain B (CLTB) and Ras-related protein Rab7a (RAB7A) to trigger clathrin-mediated endocytosis and lysosomal degradation of CaSR, thus reducing its membrane abundance. This degradative program was further validated by multiplex immunofluorescence in TOMM20highCHGAhigh pathological oxyphil cells in human SHPT tissues. To translate these mechanistic findings into a clinically actionable strategy, we repurposed the clinically approved lysosomal inhibitor hydroxychloroquine (HCQ) to block this CaSR degradation pathway. In patient-derived xenograft (PDX) mouse models, co-administration of HCQ and cinacalcet acted synergistically to restore membrane CaSR expression, normalize serum PTH and calcium levels and suppress parathyroid tumor growth more effectively than monotherapies. Collectively, our single-cell-guided study identifies an NFIC-driven endo-lysosomal program as a previously unrecognized mechanism underlying CaSR downregulation and calcimimetic resistance in SHPT, and establishes HCQ repurposing as a clinically tractable therapeutic strategy for patients with refractory SHPT.

cell biology↗

bioRxiv2026

A natural soil-derived microbiota reshapes nitrogen form and plant mineral nutrition

Nitrogen form in soil has a major influence on plant growth and mineral nutrition, yet whether and how nitrogen form is controlled by microbiota in natural soils remains poorly understood. Here we show that, in a high-organic-matter soil from Danish nature, the native soil microbiota determines nitrogen form and thereby controls plant mineral nutrition. Eliminating the microbiota by sterilization disrupted nitrification, causing ammonium accumulation and loss of nitrate, which resulted in impaired growth and a pronounced reduction in shoot Mg and Ca associated with chlorosis. Reintroduction of a simplified soil-derived microbiota restored nitrification and re-established a balanced NO{square}{square}/NH{square}{square} regime, which rescued Mg and Ca accumulation, alleviated chlorosis, and promoted plant growth. Metagenomic analyses of bulk soil, rhizosphere, and root-associated communities revealed enrichment of nitrogen-cycling functions, including nitrification-related genes, supporting the capacity of the restored microbiota to modulate nitrogen form in soil and the rhizosphere. Moreover, this microbiota alleviated mineral deficiency symptoms in an organic agricultural soil. Together, our findings reveal a natural microbiota-dependent mechanism by which soil microbes determine nitrogen form and thereby regulate plant mineral nutrition, particularly Mg and Ca homeostasis.

plant biology↗

bioRxiv2026

Fibroblast-encoded inflammatory memory orchestrates recurrent skin inflammation via NNMT-dependent metabolic remodeling

Chronic skin inflammation frequently recurs at the same anatomical sites after therapy withdrawal, implying stromal cells may encode local inflammatory memory. Here, we identified nicotinamide N-methyltransferase (NNMT) as a central metabolic-epigenetic regulator of fibroblast inflammatory memory enabling psoriasis relapse. Single-cell and spatial transcriptomics revealed that dermal fibroblasts acquire a persistent senescence-associated secretory phenotype (SASP) during inflammation, maintaining pro-inflammatory niche in resolved skin that supports CD 8+CD 103+ tissue-resident memory T cell (Trm) differentiation. Multi-omics profiling demonstrated that NNMT depletes S-adenosylmethionine (SAM), reduces H 3K 27me3 deposition, and permits sustained AP-1 occupancy at SASP gene promoters. Fibroblast-specific NNMT ablation or pharmacologic inhibition suppressed SASP activity, limited Trm accumulation, and prevented both initiation and relapse of skin inflammation in mice. These findings establish NNMT as a stromal regulator linking fibroblast metabolism to durable epigenetic memory and propose its targeting to erase inflammatory memory and achieve long-term remission in psoriasis and related immune-mediated diseases. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/721223v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@34b2f4org.highwire.dtl.DTLVardef@1d0bb89org.highwire.dtl.DTLVardef@c8277borg.highwire.dtl.DTLVardef@9825ac_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic Abstract:C_FLOATNO Proposed mechanism through which NNMT-driven fibroblast SASP facilitates the initiation and recurrence of psoriasis C_FIG

immunology↗

bioRxiv2026

A new species of Rana from Anhui, China (Anura, Ranidae)

The diversity of the brown frog genus Rana may be underestimated as the high similarity of morphological characters. A new species belonging to the genus Rana is delineated based on eight specimens obtained from the Tianma National Nature Reserve, Jinzhai County, Luan City, Anhui Province, China. The phylogenetic analysis based on three mitochondrial genes (12S, ND2, and Cyt b) and one nuclear gene (BDNF) showed that the new species formed an independent clade closely related to R. culainensis and received strong support. In addition, morphological differentiation confirmed the phylogenetic results, and both supported the validity of a new species (Rana tianmaensis sp. nov.) in the R. japonica species group. The discovery of this new species enhances peoples understanding of the biodiversity of Rana and can provide important foundational data for scientific decision-making on protected area construction, ecological conservation, and species diversity. With the inclusion of newly described species in this study, the distribution of Rana genus in China now includes 31 recognized species.

zoology↗

bioRxiv2026

Modes of programmed macrophage cell death govern outcome of cutaneous wound healing

Misregulation of tissue repair programs can severely compromise repair outcome. Timely clearance of inflammatory macrophages through regulated cell death is a prerequisite for resolution of inflammation and successful repair. How different modes of macrophage regulated cell death regulate repair and direct healing outcome remains unclear. Using inducible genetic models to trigger macrophage necroptosis (FADDiMKO) or enhance apoptosis of macrophages (cIAP1iMKOcIAP2-/-), we reveal opposing effects on the architecture of the wound tissue. Macrophage necroptosis profoundly disrupted tissue organization: FADDiMKO wounds exhibited reduced numbers of reparative (IL-4RLy6Clow) macrophages, delayed inflammatory resolution, accompanied by a hemorrhagic granulation tissue and reduced myofibroblast differentiation in the mid-phase of repair. In striking contrast, increased apoptosis preserved fundamental tissue architecture and vascular integrity, and reduced scar formation. Furthermore, single-cell transcriptomics demonstrated that macrophage necroptosis disrupts tissue-wide cellular communication networks essential for coordinated repair, in particular macrophage-fibroblast crosstalk. These findings establish that wound healing quality depends on both mode and rate of macrophage programmed death, providing a framework for therapeutic targeting of macrophages in wound healing disorders and fibrotic diseases.

immunology↗

bioRxiv2026

Neutrophil-targeted delivery of circSCMH1 unlocks an acute anti-thromboinflammatory function to restore microvascular perfusion in stroke

ObjectivesFutile recanalization (FR) after endovascular thrombectomy (EVT) is driven by neutrophil-mediated thromboinflammation, yet conventional neuroprotectants fail to address the spatiotemporal complexity of stroke injury. This study aimed to identify the clinical link between circSCMH1, traditionally viewed as a late-stage repair molecule, and FR, while evaluating its hyperacute anti-inflammatory potential via a neutrophil-targeted delivery system. MethodsWe analyzed thrombi and plasma from LVO-AIS patients stratified by functional outcomes. We engineered neutrophil-targeted lipid nanoparticles (circSCMH1@pepLNP) for delivery in a mouse transient middle cerebral artery occlusion model. Therapeutic outcomes were evaluated through infarct volume measurement, histological assessment of NETosis, and intravital two-photon microscopy to monitor real-time neutrophil dynamics and capillary stalling. ResultsClinical analyses showed circSCMH1 was significantly downregulated in FR patients, with its levels negatively correlated with NET burden. Furthermore, circSCMH1-negative neutrophils exhibited a higher propensity for NETosis within the thrombus microenvironment. In mice, circSCMH1@pepLNP achieved specific neutrophil delivery, significantly reduced infarct volume, and suppressed the expression of citrullinated histone H3 and neutrophil elastase. Intravital two-photon and laser speckle imaging further confirmed that this intervention attenuated neutrophil adhesion, increased migratory velocity, and alleviated capillary stalling, thereby restoring cortical microvascular perfusion. ConclusionsOur findings associate neutrophil-specific circSCMH1 downregulation with clinical FR in LVO-AIS. Targeted intracellular delivery reveals an acute anti-thromboinflammatory function that complements established reparative properties, proposing a novel adjunctive approach for EVT to address the spatiotemporal complexity of stroke and improve clinical outcomes.

neuroscience↗

bioRxiv2026

Ancestral secretory programs underlie the evolution of morphological innovations across Spiralia

Understanding how morphological innovation arise from ancestral genetic and cellular systems remains a major challenge in evolutionary biology. Molluscan shells represent one of the most diverse morphological novelties within Spiralia and have been central to the ecological and evolutionary diversification of molluscs. However, the cellular basis of shell formation and the evolutionary origin of shell-forming cell types remain poorly understood. Here, we present a single-cell transcriptomic atlas of the Pacific oyster (Crassostrea gigas) mantle and show that molluscan shell-forming cell types are evolutionarily recent innovations built upon ancestral epithelial secretory systems of spiralians. We identify five spatially segregated shell-forming epithelial cell types, and demonstrate that larval and adult shell-forming cells are developmentally independent and characterized by transcriptomes enriched for evolutionarily young genes. Cross-species cell-type comparisons further reveal that oyster shell-related genes are embedded within conserved epithelial and secretory programs across spiralians. Together, we propose that a substantial genetic foundation for shell formation was already present in the last common ancestor of Spiralia, and that molluscan shell diversity arose through repeated co-option of ancestral genetic programs coupled with novel genes. Our study provides a framework for understanding how ancient cellular architectures can be repeatedly reconfigured to generate morphological novelty during evolution.

evolutionary biology↗

bioRxiv2026

DNA replication initiation causally sets the added mass for cell division in Escherichia coli

Faithful genome inheritance requires cell division to be precisely coordinated with DNA replication. The classical Cooper-Helmstetter paradigm posited that division occurs at a roughly constant time after replication initiation (initiation-to-division "ID-timer" model). This has since been challenged by conflicting "adder" phenomena, leaving the primary signal for division a fundamental enigma. Here, we resolve these discrepancies by establishing that cell division in Escherichia coli obeys a universal "ID-adder" rule: addition of a defined size increment from replication initiation. This rule is invariant across the physiological range of nutrition-affected growth rates, whereas other versions of the adder phenomenon are emergent properties shaped by inter-cycle correlations. Through population-level perturbations of initiation mass, division machinery, and replication termination, we demonstrate that replication initiation directly and causally sets the division schedule. This principle operates independently of replication termination and division protein levels, providing a robust mechanism for coordinating the genome duplication with the cell division cycle.

microbiology↗

bioRxiv2026

An immune-poised state of human bronchial epithelial cells mediates RSV resistance in adults

Respiratory syncytial virus (RSV) impairs STAT3 activation in infected ciliated cells in infants, but not adults, causing apoptosis to facilitate virus spread. How age regulates the STAT3 response to RSV in human bronchial epithelial cells (BEpiCs) is unknown. Here, we identify an age-associated immune-poised physiological state in human bronchial basal stem cells (BSCs) and progeny BEpiCs, rendering robust RIG-I to guard against the inactivation of RIG-I-STAT3 signaling by RSV nonstructural protein 2. In contrast, infant BEpiCs are vulnerable to such inactivation by RSV due to lower RIG-I levels. We show that acute respiratory viral infection in specific pathogen-free mice, rather than physical age, triggered sustained epigenetic and transcriptomic remodeling in BEpiCs that resembled age-associated changes in human BEpiCs. In addition, cytokine pretreatment of human neonatal BSCs induced an adult-like immune-poised state that was maintained in progeny BEpiCs to protect against RSV. Therefore, respiratory infection and inflammation during a lifetime imparts the effect of age to BSCs, which fortifies RIG-I in progeny cells to mediate RSV resistance.

microbiology↗

bioRxiv2026

Programmed Double-stranded RNA Formation Enables Meiotic Stage Transitions

Cell fate transitions rely on extensive transcriptional activation mediated by transcription factors, yet the equally important processes that ensure the selective removal of pre-existing mRNAs remain elusive. We uncover widespread formation of double-stranded RNA (dsRNA) during early-to-middle meiosis using quantitative RNA structure analysis, and validate hundreds of natural antisense transcripts (NATs) through long-read sequencing. These NATs are induced by meiosis-specific transcription factors, including Ndt80p, and pair with sense mRNAs to drive cytoplasmic aggregation of the resulting dsRNAs. These dsRNA aggregates are subsequently transported to the vacuole for clearance, likely via autophagy. This pathway selectively eliminates mRNAs before metaphase I, including NDJ1, which encodes a meiotic cohesion protein that would otherwise block chromosome segregation. Our study reveals a physiological role for large-scale dsRNA formation, and highlights a simple but powerful model: the same transcription factors that activate mRNAs required for a specific developmental stage also program the synthesis of NATs that promote removal of transcripts from the preceding stage, thereby driving bidirectional transcriptome reprogramming.

cell biology↗

bioRxiv2026

RNA Structure Coordinates Translation Across the Meiotic Program

mRNA structure clearly modulates translation efficiency for individual transcripts, yet its role in coordinating translation across many transcripts remains poorly defined. Meiosis offers a compelling test case, involving large-scale gene expression changes coordinated across hundreds of mRNAs under conditions where transcription is constrained by chromosome condensation. We profiled mRNA structures across yeast meiosis, generating a high-resolution structurome encompassing ~70% of annotated mRNAs, including multi-time-point measurements for 2,084 transcripts. Transcripts upregulated during meiosis generally adopt flexible structures that enhance translation, whereas mRNAs with complex 5' UTR and coding-region structures show suppressed translation, indicating that RNA structure globally shapes meiotic translation. We further observed a high-low-high oscillation in cytoplasmic RNA helicase levels across meiosis. Together, these findings support a model in which RNA structure and helicase expression act jointly to program stage-specific translation of hundreds of mRNAs, with highly structured transcripts selectively translated at late stages. Consistent with this model, disrupting the structure of the abundant transcript CCW22, or altering Ded1p helicase levels, impaired meiotic progression in an RNA structure-dependent manner. Our study reveals that the concerted action of RNA structure and helicases coordinates cell-wide translation dynamics to meet stage-specific demands, especially critical when transcription is limited during meiotic divisions.

genomics↗

bioRxiv2026

A Bear-Specific Coding Exon in TMEM41B Is Associated with Cold Adaptation

AbstractBears exhibit an unusual form of hibernation in which core body temperature remains relatively high despite profound suppression of whole-body metabolism. How such a warm yet hypometabolic state is achieved remains poorly understood. Here, through integrative analysis of 238 RNA-seq datasets spanning seven species, we identify transmembrane protein 41B (TMEM41B) as an evolutionarily conserved factor associated with thermogenic capacity. Loss of Tmem41b in mice and Drosophila results in severe cold intolerance, whereas its overexpression enhances thermogenic performance, supporting a conserved role in heat production. Comparative genomic analyses reveal a bear-specific 51-amino acid N-terminal extension in TMEM41B, arising from a 5' untranslated region mutation that converts a premature stop codon into coding sequence. Interactome profiling indicates that this bear-specific isoform differs from the canonical TMEM41B in its protein interaction landscape, including reduced association with components of mitochondria-associated endoplasmic reticulum membranes such as voltage-dependent anion-selective channel protein 1 (VDAC1). Consistent with this altered interaction profile, the extended isoform is associated with reduced mitochondrial oxidative activity. Functional analyses further suggest that the 51- amino acid extension modulates multiple cellular programs, including suppression of oxidative phosphorylation and myogenic differentiation alongside activation of osteogenic pathways, collectively biasing cells toward a hypometabolic state. Notably, expression of the polar bear TMEM41B isoform in mice induces a torpor-like phenotype under fasting conditions. Together, these findings identify TMEM41B as a conserved regulator of thermogenic capacity and suggest that evolutionary modification of its N terminus may contribute to metabolic suppression and energy conservation during bear hibernation.

evolutionary biology↗