Biology subjects

Wang, B.

Publications and source records attributed to Wang, B..

At least 91 records · Page 5Linked to original sources

bioRxiv2026

ArchaicSeeker 3.0: A deep-learning framework for scalable, haplotype-resolved inference of archaic introgression

Archaic introgression has left a significant mark on human genetic diversity, but reliably identifying introgressed segments remains a major challenge, especially with complex demographic histories and limited sample sizes. Existing methods often rely on demographic assumptions or cohort-specific parameter fitting, which compromises robustness and scalability. We introduce ArchaicSeeker 3.0 (AS3), a deep-learning framework designed for haplotype-resolved detection of archaic introgression. AS3 integrates a tract-scale sequence model with an overlap-aware reassembly approach and boundary refinement, enabling accurate, boundary-coherent reconstruction of introgressed segments across diverse genomic contexts. By leveraging a simulation-trained model, AS3 avoids inference-time recalibration, offering stable performance across unrepresented demographic scenarios and small cohorts. In extensive simulations, AS3 outperforms existing methods in precision, recall, and F1 score, while providing more continuous segments with accurate boundary localization. It demonstrates robustness in small-target regimes and varying marker densities. Applied to 3,453 genomes from 209 populations, AS3 shows strong concordance with existing introgression callers and identifies additional introgressed regions, including high-frequency AS3-specific introgressed segments supported by locus-level haplotype and phylogenetic analyses. AS3 provides a scalable, robust solution for detecting archaic introgression from single individuals to large biobank datasets, marking a significant advancement in the field of local ancestry inference and opening new possibilities for the study of human evolutionary genetics. ArchaicSeeker 3.0 is available at https://github.com/Shuhua-Group/ArchaicSeeker3.0.

bioinformatics↗

bioRxiv2026

Evidence for an Organometallic Species Formed in the ArsL Reaction

The radical S-adenosylmethionine (SAM) superfamily comprises over 800,000 unique sequences of enzymes that catalyze more than 100 distinct reactions. Canonical radical SAM (RS) enzymes are composed of a full or partial triose phosphate isomerase fold and contain a highly conserved CX3CX2C motif. The cysteines in the conserved motif ligate an [Fe4S4] cluster used in the reductive cleavage of SAM to yield methionine and a 5'-deoxyadenosyl 5'-radical (5'-dA*). The 5'-dA* is typically used to initiate catalysis by abstracting a hydrogen atom from a bound substrate, yielding 5'-deoxyadenosine and a substrate radical. ArsL, a recently characterized RS enzyme involved in the biosynthesis of the antibiotic arsinothricin (AST), catalyzes a reaction that deviates from the canonical RS reaction, forming methylthioadenosine and a 3-amino-3-carboxypropyl radical (ACP*). The ACP* is used to construct a carbon-arsenic bond to form the organoarsenic compound hydroxyarsinothricin (AST-OH), the penultimate enzymatic step in forming AST. While investigating how ArsL suppresses the formation of the 5'-dA* in favor of the ACP*, we discovered that ArsL forms a unique organometallic species containing a bond between the gamma carbon of ACP and the unique iron of the [Fe4S4] cluster. We propose that ArsL uses this novel species to generate a sufficiently electrophilic carbon that can be attacked by arsenous acid, thereby forming the carbon-arsenic bond.

biochemistry↗

bioRxiv2026

Dual inhibition of GTP-bound (ON) and GDP-bound (OFF) KRASG12C suppresses PI3Kα and leads to potent tumor inhibition

Current approved KRASG12C inhibitors covalently bind the inactive GDP-bound (OFF) form of KRASG12C. Recently, KRASG12C inhibitors that selectively bind to the GTP-bound (ON) form of both KRASG12C (ON) and (OFF) forms have been reported and entered clinical testing. In principle, KRASG12C (ON) inhibitors may be less susceptible to adaptive mechanisms that promote resistance to (OFF) inhibitors, however the specific mechanisms that differentiate the activity of (ON) versus (OFF) inhibition are not well understood. We profiled the activity of BBO-8520, a covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, in KRASG12C-mutant non-small cell lung cancer models. BBO-8520 exerted more potent and sustained inhibition of KRASG12C and anti-tumor activity in vitro and in vivo compared with sotorasib, a KRASG12C (OFF)-only inhibitor. While cells treated with BBO-8520 or sotorasib both exhibited feedback reactivation of MAPK signaling driven by wild-type HRAS/NRAS isoforms, more durable suppression of KRASG12C by BBO-8520 was associated with decreased PI3K-AKT activation in vitro. Disruption of the interaction between RAS and PI3K using a novel protein:protein interaction inhibitor suppressed PI3K-AKT activation and increased the tumor response to sotorasib to a similar level as BBO-8520. Moreover, in some contexts, disruption of RAS-PI3K further increased the anti-tumor activity of BBO-8520 monotherapy. These results reveal mechanistic differences between KRAS (ON) and (OFF) inhibitors, highlight the importance of PI3K-AKT signaling in driving resistance to KRAS inhibition in lung cancer, and suggest combination strategies that suppress PI3K-AKT to improve the response to KRAS inhibitors.

cancer biology↗

bioRxiv2026

Engulfment by brain macrophages in a short-lived vertebrate

Engulfment by macrophages is critical for waste clearance in the vertebrate brain. Understanding clearance mechanisms may open new therapeutic possibilities to counter brain aging and neurodegenerative diseases. However, few in vivo models exist to study engulfment in the brain and characterize this process during aging and across species. Here we present a genetic model for secretion of a fluorescent protein by neurons in the brain of the African turquoise killifish, the shortest-lived vertebrate that can be bred in captivity. We use this model to identify a population of brain macrophages in the killifish responsible for engulfment of material from the brain extracellular space. Intriguingly, many of these cells bear similarities to mammalian border-associated and monocyte-derived macrophages, rare subsets of macrophages in mouse and human brains noted for their engulfment capabilities. We also find that in our model, killifish brain macrophages decline in engulfment capacity with age. This work highlights how vertebrate brain macrophages, particularly those at brain border regions, can play a critical role in clearance and provides an opportunity to test interventions that can boost engulfment by these macrophages to promote brain resilience in old age and disease.

cell biology↗

bioRxiv2026

Normal Aging Limits Cortical Network Reorganization and Behavioral Recovery after Experimental Stroke

Stroke is the leading cause of chronic disability in the United States, and advancing age is associated with worse recovery. Despite this, relatively little is known about how aging influences the repair and reorganization of neural circuits and large-scale cortical networks after stroke. To address this question, we compared cortical network dynamics and behavioral recovery after focal photothrombotic stroke in forepaw somatosensory cortex in young (3-month-old) and aged (18-month-old) Thy1-GCaMP6f mice. Both young and aged mice developed significant somatomotor deficits after stroke; however, only young mice exhibited substantial behavioral recovery despite similar infarct volumes across groups. Two age-dependent effects on cortical network function emerged. First, somatosensory-evoked activity and somatosensory functional connectivity were disrupted in both cohorts early after stroke, but their trajectories diverged over time. Forepaw-evoked GCaMP responses in the affected cortex were similarly reduced in both groups early after stroke; yet by 7 weeks, responses recovered in young mice but remained persistently depressed in aged animals. Likewise, bihemispheric somatosensory functional connectivity was initially disrupted in both groups but improved between 1 and 7 weeks only in young mice. Second, global temporal measures of network function evolved differently after stroke. At baseline, stimulus-locked fidelity and interhemispheric coherence were higher in young than aged mice, but after stroke, these measures declined in young animals to levels comparable to aged mice and did not recover by 7 weeks. Stroke also altered large-scale cortical entrainment dynamics, and reductions in cortical entrainment area between baseline and 1-week post-stroke predicted long-term behavioral recovery across animals. Together, these findings indicate that impaired behavioral recovery in aged mice reflects a failure of damaged somatosensory networks to reorganize, whereas recovery in young mice occurs despite persistent degradation of global network fidelity and coherence. These results highlight age-dependent mechanisms of circuit repair after stroke and suggest a potential network-level basis for chronic deficits in stroke survivors. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=65 SRC="FIGDIR/small/720447v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@1f23999org.highwire.dtl.DTLVardef@1a3a433org.highwire.dtl.DTLVardef@712dd5org.highwire.dtl.DTLVardef@780eaa_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2026

Selective Editing and Functionalization of the Mammalian Lipidome

Lipids exhibit extraordinary molecular diversity, yet tools to selectively manipulate defined lipid classes in living cells are lacking. Here we show that lipid tail structure biases metabolic fate, enabling the design of synthetic lipid analogs with programmable metabolic selectivity. This approach enables selective cellular production of distinct lipid species or subclasses, including types of neutral lipids, phospholipids, sphingolipids, and ether lipids, without genetic or enzymatic perturbation. We further couple metabolic selectivity to chemical functionalization using bifunctional lipids, in which one modification directs metabolic flux and a second enables bioorthogonal tagging. Using this strategy, we achieve selective in situ labeling of different lipid pools in living cells. Together, our work establishes a chemical biology strategy that enables unprecedented precision in modulating, functionalizing, and rewiring the mammalian lipidome.

cell biology↗

bioRxiv2026

High Purity Differential Expression of Genes across Spatial Domains

Spatial transcriptomics maps gene expression within tissue architecture, offering deep insights into cellular function. A key yet overlooked phenomenon is the systematic imbalance in gene regulation within spatial domains, contrasting with traditional analyses. We define and validate this as a prevalent hallmark--High-Purity Differential Expression (HiP-DEP)--where genes in a domain shift predominantly in one direction (i.e., predominantly up- or downregulated). We introduce a Spatial Purity index to quantify it. Analysis of 190 diverse datasets across diverse tissues, diseases, and technologies revealed that spatial domains possess significantly higher purity than conventional bulk (p = 5.4 x 10-11) or single-cell data (p = 6.9 x 10-14), establishing HiP- DEP as a core hallmark of spatial biology. Using our HiP-DEP framework, we show its utility in: decoding core oncogenic regulation and its spatial gradient in breast cancer; uncovering hidden phenotypic divergence between morphologically similar Alzheimers plaques; and identifying active cellular communication niches in normal brain tissue. By shifting focus from individual genes to coordinated transcriptional programs, HiP-DEP provides a new paradigm for precision spatial omics analysis.

bioinformatics↗

bioRxiv2026

PALAEOROBOTICS UNCOVERS DEVASTATING MAMMALIAN TAIL STRIKE DYNAMICS

Extant animals occupy only a fraction of evolutionary design space, leaving many extinct morphologies without living analogues for functional testing. We combined comparative anatomy of 32 glyptodont species with a life-sized palaeorobotic tail rig to determine strike severity in club-tailed giant from the Pleistocene megafauna Doedicurus. The robophysical model, informed by fossil geometry and inertia, matched simulated fossil-tail collision momentum (98-105%) and generated peak forces of 81.1 kN at 6.4 m{middle dot}s-{superscript 1}, with an impulse of 427 N{middle dot}s, far exceeding equine extremity fracture forces. Peak force scaled near-linearly with strike velocity, implying [~]183 kN at projected top speed of 15 m{middle dot}s-{superscript 1}. Measurements suggest Doedicurus delivered high-severity strikes, supporting antipredator defence as primary selective driver of extreme tail weaponization, and establish palaeorobotic validation of extinct animal biomechanics.

bioengineering↗

bioRxiv2026

Scaling Multiplex qPCR Primer Design to 1000-plex using the Degenerate Incomplete Multiplex Primer List Extension (DIMPLE) Algorithm

Massively multiplexed qPCR is primarily constrained by increasing primer dimer formation as the number of distinct primers in a single reaction increases. Previous multiplex primer design algorithms either fail to sufficiently suppress primer dimers at 100+ plex, or take exceedingly high amounts of computational resources to complete. Here, we present DIMPLE, a linear-runtime primer design algorithm that effectively generates 10,000+ primers to amplify thousands of potential amplicons in a single qPCR reaction. As one clinical demonstration of this algorithm, we designed an assay to detect 2,302 distinct KMT2A gene fusion subtypes using 204 primers in a single tube. In contrast to FISH and convention NGS approaches with 2% variant allele frequency (VAF) limit of detection, our DIMPLE qPCR assay was able to analytically detect gene fusions down to 0.05% VAF. We also constructed proof-of-concept multiplex qPCR panels for additional oncology gene fusions, multiplex pathogen detection, and DNA methylation markers. The scalability and low computational cost DIMPLE are complementary to new instrument platforms for massively multiplex qPCR readout for enabling rapid, point-of-care nucleic acid testing.

bioengineering↗

bioRxiv2026

Zebrafish Functional Screening of FDA-Approved Drugs for Autosomal Dominant Retinitis Pigmentosa Caused by RHODOPSIN Q344X Mutation

Retinitis Pigmentosa (RP) is a group of inherited retinal degenerations for which most subtypes lack effective drug treatments. This challenge is particularly critical for autosomal dominant (ad) RP, which is often unsuitable for gene replacement therapy. To address this challenge, we screened an FDA-approved compound library using a zebrafish adRP model expressing a human RHODOPSIN transgene with the Q344X mutation. The screen evaluated drug effects on larval visual behavior by assessing the visual-motor response (VMR). Four compounds significantly improved VMR in Q344X zebrafish: amitriptyline, difluprednate, maprotiline, and prednisolone. Further characterization revealed that these hits act through distinct mechanisms, including reducing rod death, promoting rod neogenesis, and enhancing the function of extraocular photoreceptors. Together, these findings demonstrate the potential to repurpose these drugs for adRP caused by the RHO Q344X mutation, providing preclinical candidates and revealing potential targets for future drug development.

neuroscience↗

bioRxiv2026

Detection of a sequence feature for recursive splicing

RNA splicing is directed by cis-acting sequence signals interacting with trans-acting factors to remove introns from newly transcribed pre-mRNA, joining exons to generate mature mRNA. Splicing happens far more often than observed exon-exon junctions in mRNA. As one contributing process, the spliceosome progressively removes large introns in small segments by recursive splicing, instead of splicing the whole intron at one time. However, the cis-acting sequences associated with recursive splicing have not been identified. Using probabilistic mixture models, we found that recursive splicing occurs more frequently in first introns, which are typically longer, and exhibit a distinct CG-rich sequence feature in the sequences flanking the upstream 5SS, and depletion of CGs in the downstream polypyrimidine tract. Remarkably, recursive splicing is also more frequent in downstream introns of genes containing first introns with these properties. Mechanistically, these data suggest that early events in RNA synthesis and processing influence the prevalence of recursive splicing for the rest of the transcript. Finally, we developed a sequence-dependent classifier for recursive splicing, which we tested with a novel medium-throughput primer extension assay. In summary, the usage of recursive splicing sites is established at the beginning of RNA synthesis through newly-identified sequence motifs flanking both ends of the first intron.

genomics↗

bioRxiv2026

Vitamin C-Induced Photo-Redox Threshold Enables High-Fidelity Volumetric Printing of Pristine Collagen

Tomographic volumetric printing (TVP) enables rapid fabrication of complex, centimeter-scale 3D architectures. TVP of pristine proteins like collagen is attractive because it better preserves native bioactive motifs that regulate cell-matrix signaling. However, direct TVP of collagen remains challenging because dityrosine crosslinking, driven by visible-light-activated Ru(II)bpy32+/sodium persulfate (SPS), lacks an effective inhibitory mechanism. This results in near-immediate crosslinking upon exposure to light, which leads to an insufficient nonlinear threshold response that fails to suppress background curing. Here, we introduce vitamin C (L-ascorbic acid) as a biocompatible redox regulator to overcome this limitation. UV-Vis kinetics demonstrate that vitamin C suppresses Ru(III) accumulation and scavenges persulfate radicals within Ru/SPS system. This dual action generates a critical photo-redox and crosslinking threshold that inhibits dityrosine formation until vitamin C is depleted. Thereby the threshold response needed for TVP is successfully established, which enables high-fidelity volumetric printing of native collagen. Post-printing construct densification ([~]53% shrinkage) further improves feature resolution (80 {micro}m positive; 120 {micro}m negative) and yields mechanically stable and highly stretchable hydrogels (up to 180% strain). Collagen resin with vitamin C supports both cell seeding post-printing and cell-laden printing with high cell density and viability, enabling the rapid biofabrication of cell-instructive 3D microenvironments. Table of Contents (ToC) O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=37 SRC="FIGDIR/small/717972v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@742a83org.highwire.dtl.DTLVardef@930c06org.highwire.dtl.DTLVardef@1fa7f08org.highwire.dtl.DTLVardef@aa22bb_HPS_FORMAT_FIGEXP M_FIG C_FIG Tomographic volumetric printing (TVP) of native proteins is limited by uncontrolled background crosslinking. Here, vitamin C is introduced as a biocompatible redox-regulator to establish a tunable nonlinear polymerization threshold response for TVP. This strategy effectively suppresses background crosslinking and enables high-fidelity printing of pristine collagen. Subsequent post-print densification yields robust, elastic, and cell-compatible constructs with enhanced resolution for tissue engineering applications.

bioengineering↗

bioRxiv2026

Complete Telomere-to-Telomere Assembly of the Y Chromosome in the Chinese Quartet

The complete assembly of the human Y chromosome remains a formidable task due to its highly repetitive, palindromic, and heterochromatic architecture. While complete telomere-to-telomere (T2T) assemblies have recently been generated for select individuals, high-quality, gapless Y chromosome references for East Asian lineages--specifically within well-characterized multi-omics reference cohorts--remain scarce. The Chinese Quartet (CQ), comprising monozygotic twin daughters and their parents, represents a premier national reference material system for genomic standardization. However, because the female offspring inherited their father's X chromosome rather than his Y chromosome, previous pedigree-based T2T assemblies (CQ v3.2) lacked a gapless Y chromosome sequence. Here, we present a complete, gapless T2T assembly of the Y chromosome (designated CQ_chrY) from the father of the CQ. This assembly was generated by integrating Oxford Nanopore Technologies ultra-long reads, PacBio high-fidelity reads, and Hi-C data, resulting in a sequence of 68.50 Mb. The assembly shows exceptional base accuracy (QV = 57.54) and structural assembly quality (CRAQ AQI = 99.781). We completely resolved the 40.09 Mb Yq12 heterochromatic region, a ~940 kb centromeric higher-order repeat array, and annotated 96 protein-coding gene models evaluated against GENCODE/T2T-Y standards, alongside 57.59 Mb (84.07%) of repetitive elements. CQ_chrY serves as a complementary paternal resource extending the CQ reference platform, providing a robust foundation for population genetics, structural variation analysis, and East Asian genomic standardization.

genomics↗

bioRxiv2026

A correlational study of ABCA3 and SCN4B as exercise-related biomarkers of patients with Stanford type A aortic dissection

BackgroundAccumulating evidence indicates that moderate exercise may reduce the incidence of Stanford type A aortic dissection (TAAD), but the specific mechanisms remain unclear. This study aims to identify exercise-related biomarkers in TAAD patients and to investigate their underlying mechanisms. MethodsTranscriptome data related to TAAD and exercise-related genes were obtained from publicly available databases. Candidate biomarkers for TAAD were identified through an integrative approach incorporating differential expression analysis, machine learning, and expression level assessment, leading to the construction of a diagnostic model. Subsequently, functional enrichment, immune infiltration, regulatory network analysis, and computational drug prediction were conducted to systematically investigate the pathological mechanisms and translational potential of the indentified biomarkers. ResultsABCA3 and SCN4B were identified as exercise-related biomarkers in TAAD progression. A nomogram incorporating these two biomarkers exhibited strong diagnostic performance for identifying the disease. Functional enrichment analysis revealed potential involvement of these biomarkers in disease progression through pathways including circadian rhythm regulation and ribosome biosynthesis. Additionally, immune cells like M1 macrophages and naive B cells, as well as regulatory factors including hsa-miR-1343-3p and XIST, were found to be involved in this process. Finally, zonisamide and MRS1097 were identified through computation prediction as potential therapeutic drugs. ConclusionABCA3 and SCN4B were identified as exercise-related biomarkers associatied with TAAD and represent potential valuable targets for both diagnosis and treatment strategies.

bioinformatics↗

bioRxiv2026

Deep learning based behavioral analysis in a neonatal rat model of hypoxic ischemic brain injury

Hypoxic-ischemic (HI) brain injury in neonates is one of the leading causes of lifelong neurological disability. Behavioral tests in preclinical rodent models are widely used to assess motor and cognitive outcomes after HI injury; however, these assays usually depend on subjective and labor-intensive manual scoring. Recent advances in markerless pose estimation offer new opportunities for automated and reproducible behavioral quantification in animal and infant recordings, but their use in neonatal HI preclinical studies remains limited. Wistar rat pups underwent HI injury using the Rice-Vannucci model at postnatal day 7 (P7). Three developmental behavioral tests included righting reflex (P8), negative geotaxis (P14), and wire hang (P16), were recorded and analyzed by both a human rater and an automated pipeline using DeepLabCut (DLC), an open source markerless pose estimation framework. Automated measurements were compared with manual scores using Intraclass Correlation Coefficients (ICC), Bland-Altman analysis, and Pearson correlation. DLC-derived measurements demonstrated strong agreement with manual scoring across all assays. ICC values were 0.929 (95% CI 0.648-0.971) for righting reflex, 0.965 (0.888-0.989) for negative geotaxis, and 0.958 (0.876-0.985) for wire hang. An automated behavioral analysis framework integrating DLC-based pose estimation with rule based quantification and supervised machine learning offers a reliable and objective alternative to manual scoring in neonatal HI models, enabling more efficient and reproducible behavioral assessment.

neuroscience↗

bioRxiv2026

Global genomic diversity of the selfing nematode Caenorhabditis tropicalis correlates with geography

Self-fertilization reduces genetic diversity compared to outcrossing and hypothetically decreases the ability to adapt to diverse environments. Among Caenorhabditis nematodes, self-fertilization evolved three times independently in Caenorhabditis elegans, Caenorhabditis briggsae, and the more recently discovered Caenorhabditis tropicalis. To survey C. tropicalis genetic relatedness, the influence of geography and niche on species-wide variation, and the signatures of selection, we collected 785 wild strains, sequenced their genomes, and identified 622 distinct genotypes (isotypes). In contrast to C. elegans and C. briggsae, C. tropicalis relatedness shows substantial association with geography and no transcontinental selective sweeps or broadly sampled isotypes. Populations from the Hawaiian Islands or Taiwan harbor more genetic variation than populations from the Caribbean or Americas, suggesting a Pacific species origin similar to other members of the Elegans subclade. Punctuated genomic regions of extreme genetic variation pervade the genome. These hyper-divergent regions (HDRs) comprise less than 6% of the reference genome in any given strain despite harboring 73% of all variant sites and are enriched for genes likely involved in environmental adaptation. HDRs represent a shared genomic feature of self-fertilizing Caenorhabditis nematodes despite their independent evolutionary origins and suggest a mechanism to explain worldwide distributions despite low species-wide levels of genetic variation.

genomics↗

bioRxiv2026

A Haplotype-resolved Telomere-to-Telomere Pig Genome

Haplotype-resolved telomere-to-telomere (T2T) pig genomes have not been reported, but may be essential for xenotransplantation and interspecies chimerism. Here we describe fully phased paternal and maternal T2T assemblies of an Erhualian pig (Ssc_EHL), enabling chromosome-scale reconstruction at base resolution. We uncover 2,498 (paternal haplotype) and 2,577 (maternal haplotype) protein-coding loci previously unresolved in Sscrofa11.1, while maintaining high concordance for anchored gene models between haplotypes. Applying this haplotype-resolved T2T annotation to publicly available pig-to-human kidney xenograft transcriptomes further allows the resolution of xenograft cell states and reveals newly resolved, cell-type-enriched genes. Cross-species synteny and orthology analyses against human identified a subset of high-confidence pig-specific genes with limited human counterparts, thus, refining the genomic basis of interspecies divergence. By integrating these orthology features with organ transcriptomes, we further defined an Interspecies Chimerism Compatibility score to prioritize organ-enriched, highly conserved loci with minimal redundancy imbalance, providing haplotype consistent targets for engineering organ-deficient pigs. Together, this haplotype-resolved T2T pig genome provides a foundational resource for mechanistic studies and rational genome engineering in xenotransplantation and interspecies chimerism.

genomics↗

bioRxiv2026

NFYA regulates two sequential genome-wide transcriptional activation events during oocyte-to-embryo transition

Primordial follicle oocyte activation (PFA) and zygotic genome activation (ZGA) represent two major waves of transcription activation respectively required for oocyte growth and preimplantation embryo development. Although many shared molecular hallmarks between PFA and ZGA suggest potential common factors and mechanisms driving both waves of transcriptional activation, such factors are yet to be identified. Here we demonstrate that the pioneer factor NFYA belongs to such regulators. Oocyte-specific Nfya deletion impairs open chromatin establishment and transcriptional activation during PFA, which triggers non-canonical ferroptosis leading to early folliculogenesis failure. Moreover, acute NFYA depletion in zygotes causes defective ZGA and predominantly two-cell embryo arrest. Mechanistically, although NFYA exhibits distinct chromatin-binding preferences predominantly targeting promoters during PFA and enhancers during ZGA, pre-occupied NFYA regulates chaperones and histone genes in both PFA and ZGA through conserved promoter binding. Together, our studies establish NFYA as a multifaceted regulator of genome activation during both PFA and ZGA. HighlightsO_LINFYA deficiency impairs primordial follicle oocyte activation (PFA) and triggers non-canonical ferroptosis resulting in early folliculogenesis failure C_LIO_LINFYA depletion impairs zygotic genome activation (ZGA) and causes predominantly 2-cell embryo arrest C_LIO_LIConserved and distinct NFYA-chromatin interactions drive both PFA and ZGA C_LIO_LIChaperones are pre-occupied and regulated by NFYA and their inhibition impairs both PFA and ZGA. C_LI

developmental biology↗