Biology subjects

Xu, J.

Publications and source records attributed to Xu, J..

At least 289 records · Page 16Linked to original sources

bioRxiv2024

Generation of cultured beef from bovine embryonic stem cells

Bovine embryonic stem cells (bESCs) serve as an optimal source for generating muscle and fat tissues. However, systematic methodologies for creating cultured beef from bESCs have not yet been reported. Here, we successfully established a bESC line and formulated a specialized culture medium that supports cell pluripotency in both two-dimensional (2D) and three-dimensional (3D) cultures. Additionally, we have also developed serum-free and transgene-free protocols that efficiently differentiate bESCs into muscle and fat cells. These differentiated cells were validated at the transcriptional and protein levels. Furthermore, we devised a method using high moisture stretched plant-based protein scaffolds for incorporating differentiated muscle and fat cells derived from bESCs, producing an innovative plant-cell hybrid cultured beef. These advancements provide a solid foundation for future cultured beef production using pluripotent stem cells.

bioengineering↗

bioRxiv2024

PROPERMAB: an integrative framework for in silico prediction of antibody developability using machine learning

Selection of lead therapeutic molecules is often driven predominantly by pharmacological efficacy and safety. Candidate developability, such as biophysical properties that affect the formulation of the molecule into a product, is usually evaluated only toward the end of the drug development pipeline. The ability to evaluate developability properties early in the process of antibody therapeutic development could accelerate the timeline from discovery to clinic and save considerable resources. In silico predictive approaches, such as machine learning models, which map molecules to predictions of developability properties could offer a cost-effective and high-throughput alternative to experiments for antibody developability assessment. We developed a computational framework, PROPERMAB, for large-scale and efficient in silico prediction of developability properties for monoclonal antibodies, using custom molecular features and machine learning modeling. We demonstrate the power of PROPERMAB by using it to develop models to predict antibody hydrophobic interaction chromatography retention time and high-concentration viscosity. We further show that structure-derived features can be rapidly and accurately predicted directly from sequences by pre-training simple models for molecular features, thus providing the ability to scale these approaches to repertoire-scale sequence datasets.

bioinformatics↗

bioRxiv2024

Deciphering gene regulatory programs in mouse embryonic skin through single-cell multiomics analysis

BackgroundCell type-specific transcriptional heterogeneity in embryonic mouse skin is well-documented, but few studies have investigated the regulatory mechanisms. ResultsHere, we present high throughput single-cell chromatin accessibility and transcriptome sequencing (HT-scCAT-seq), a method that simultaneously profiles transcriptome and chromatin accessibility. We utilized HT-scCAT-seq to dissect the gene regulatory mechanism governing epidermal stratification, periderm terminal differentiation, and fibroblast specification. ConclusionsBy linking chromatin accessibility to gene expression, we identified candidate cis-regulatory elements (cCREs) and target genes crucial for dermal and epidermal development. We described cells with similar gene expression profiles that exhibit distinct chromatin accessibility statuses during periderm terminal differentiation. Finally, we characterized the underlying lineage-determining transcription factors (TFs), and demonstrated that ALX4 and RUNX2 were candidate TF regulators of the dermal papilla lineage development through in silico perturbation analysis.

developmental biology↗

bioRxiv2024

Longitudinal multi-omics reveals pathogenic TSC2 variants disrupt developmental trajectories of human cortical organoids derived from Tuberous Sclerosis Complex

Tuberous Sclerosis Complex (TSC), an autosomal dominant condition, is caused by heterozygous mutations in either the TSC1 or TSC2 genes, manifesting in systemic growth of benign tumors. In addition to brain lesions, neurologic sequelae represent the greatest morbidity in TSC patients. Investigations utilizing TSC1/2-knockout animal or human stem cell models suggest that TSC deficiency-causing hyper-activation of mTOR signaling might precipitate anomalous neurodevelopmental processes. However, how the pathogenic variants of TSC1/2 genes affect the longitudinal trajectory of human brain development remains largely unexplored. Here, we employed 3-dimensional cortical organoids derived from induced pluripotent stem cells (iPSCs) from TSC patients harboring TSC2 variants, alongside organoids from age- and sex-matched healthy individuals as controls. Through comprehensively longitudinal molecular and cellular analyses of TSC organoids, we found that TSC2 pathogenic variants dysregulate neurogenesis, synaptogenesis, and gliogenesis, particularly for reactive astrogliosis. The altered developmental trajectory of TSC organoids significantly resembles the molecular signatures of neuropsychiatric disorders, including autism spectrum disorders, epilepsy, and intellectual disability. Intriguingly, single cell transcriptomic analyses on TSC organoids revealed that TSC2 pathogenic variants disrupt the neuron/reactive astrocyte crosstalk within the NLGN-NRXN signaling network. Furthermore, cellular and electrophysiological assessments of TSC cortical organoids, along with proteomic analyses of synaptosomes, demonstrated that the TSC2 variants precipitate perturbations in synaptic transmission, neuronal network activity, mitochondrial translational integrity, and neurofilament formation. Notably, similar perturbations were observed in surgically resected cortical specimens from TSC patients. Collectively, our study illustrates that disease-associated TSC2 variants disrupt the neurodevelopmental trajectories through perturbations of gene regulatory networks during early cortical development, leading to mitochondrial dysfunction, aberrant neurofilament formation, impaired synaptic formation and neuronal network activity.

neuroscience↗

bioRxiv2024

TOMM40-APOE chimera linking Alzheimer's highest risk genes: a new pathway for mitochondria regulation and APOE4 pathogenesis

The patho-mechanism of apolipoprotein variant, APOE4, the strongest genetic risk for late-onset Alzheimers disease (AD) and longevity, remains unclear. APOEs neighboring gene, TOMM40 (mitochondria protein transport channel), is associated with brain trauma outcome and aging-related cognitive decline, however its role in AD APOE4-independently is controversial. We report that TOMM40 is prone to transcription readthrough into APOE that can generate spliced TOMM40-APOE mRNA chimera (termed T9A2) detected in human neurons and other cells and tissues. T9A2 translation tethers APOE (normal APOE3 or APOE4) to near-full-length TOM40 that is targeted to mitochondria. Importantly, T9A2-APOE3 boosts mitochondrial bioenergetic capacity and decreases oxidative stress significantly more than T9A2-APOE4 and APOE3, and lacking in APOE4. We describe detailed interactomes of these actors that may inform about the activities and roles in pathogenesis. T9A2 uncovers a new candidate pathway for mitochondria regulation and oxidative stress-protection that are impaired in APOE4 genotypes and could initiate neurodegeneration.

cell biology↗

bioRxiv2024

TRIM37 employs peptide motif recognition and substrate-dependent oligomerization to prevent ectopic spindle pole assembly

Tightly controlled duplication of centrosomes, the major microtubule-organizing centers of animal cells, ensures bipolarity of the mitotic spindle and accurate chromosome segregation. The RBCC (RING-B-box-coiled coil) ubiquitin ligase TRIM37, whose loss is associated with elevated chromosome missegregation and the tumor-prone developmental human disorder Mulibrey nanism, prevents the formation of ectopic spindle poles that assemble around structured condensates containing the centrosomal protein centrobin. Here, we show that TRIM37s TRAF domain, unique in the extended TRIM family, engages peptide motifs in centrobin to suppress condensate formation. TRIM proteins form anti-parallel coiled-coil dimers with RING-B-box domains on each end. Oligomerization due to RING-RING interactions and conformational regulation by B-box-2-B-box-2 interfaces are critical for TRIM37 to suppress centrobin condensate formation. These results indicate that, analogous to anti-viral TRIM ligases, TRIM37 activation is linked to the detection of oligomerized substrates. Thus, TRIM37 couples peptide motif recognition and substrate-dependent oligomerization to effect ubiquitination-mediated clearance of ectopic centrosomal protein assemblies.

cell biology↗

bioRxiv2024

Structural Insights into Selective and Dual Antagonism of EP2 and EP4 Prostaglandin Receptors

Prostaglandin E2 (PGE2) signaling through EP2 and EP4 receptors plays a crucial role in inflammation, pain, and cancer progression. Selective and dual antagonists of these receptors have shown promising therapeutic potential. However, the structural basis for their binding modes and selectivity remained unclear. Here, we present cryo-EM structures of human EP2 and EP4 receptors in complex with selective antagonists PF-04418948 and grapiprant, respectively, as well as the dual antagonist TG6-129. These structures reveal distinct binding pockets and interaction networks that govern antagonist selectivity and efficacy. Combining the structural data and functional studies, we uncover the key residues and structural features that differentiate EP2 and EP4 binding sites, including a unique {pi}-{pi} stacking interaction in EP2 and variations in pocket shape and charge distribution. The dual antagonist TG6-129 exhibited a novel binding mode, interacting deeply with EP2 but only shallowly with EP4 in a two-warhead manner. These findings provide a structural framework for understanding prostanoid receptor pharmacology and offer valuable insights for the rational design of improved selective and dual antagonists targeting EP2 and EP4 receptors.

biochemistry↗

bioRxiv2024

Enhanced kinase translocation reporters for simultaneous real-time measurement of PKA, ERK, and Ca2+

Kinase translocation reporters (KTRs) are powerful tools for single-cell measurement of time-integrated kinase activity but suffer from restricted dynamic range and limited sensitivity, particularly in neurons. To address these limitations, we developed enhanced KTRs (eKTRs) for protein kinase A (PKA) and extracellular signal-regulated kinase (ERK) that display high sensitivity, rapid response kinetics, broad dynamic range, cell type-specific tuning, and an ability to detect PKA and ERK activity in primary sensory neurons. Moreover, co-expression of optically separable eKTRs for PKA and ERK revealed the kinetics of expected and unexpected crosstalk between PKA, ERK, protein kinase C, and calcium signaling pathways, demonstrating the utility of eKTRs for live cell monitoring of diverse and interacting signaling pathways. These results open the door to improved live-cell and in vivo measurements of key signaling pathways in neurons, while at the same time demonstrating the importance of KTR size and NLS strength to KTR dynamics.

bioengineering↗

bioRxiv2024

Transcriptome-based identification of long noncoding RNAs (lncRNAs) across the genome of Anopheles gambiae

Anopheles gambiae is a primary malaria vector mosquito in Africa. RNA-seq based transcriptome analysis has been widely used to study gene expression underlying mosquito life traits such as development, reproduction, immunity, metabolism, and behavior. While it is well known that long non-coding RNAs (lncRNAs) are expressed ubiquitously in transcriptomes across metazoans, lncRNAs remain relatively underexplored in mosquitoes including their identity, expression profiles, and biological functions. In this study, publicly available RNA-seq datasets were leveraged to identify lncRNAs across diverse contexts, including whole mosquitoes, mosquito cells or tissues including midguts, salivary glands, and hemocytes, as well as under different physiological conditions including sugar-feeding, blood-feeding, bacterial challenges, and Plasmodium infections. Across this pool of transcriptomes, 2684 unique lncRNA genes, comprising 4082 transcripts, were identified. Following their identification, these lncRNA genes were integrated into the mosquito transcriptome annotation, which was then used as a reference to analyze both mRNAs and lncRNAs for transcriptional dynamics in different conditions. Like mRNAs, lncRNAs exhibited context-dependent expression patterns. Co-expression networks constructed using weighted gene co-expression network analysis (WGCNA) highlighted the interconnections among lncRNAs and mRNAs. Furthermore, we identified polysome-associated lncRNAs within polysome-captured transcripts, suggesting their involvement in translation regulation and coding capacity for micropeptides. A published ChIP-seq dataset was explored to correlate epigenetic signatures with transcriptional activities of lncRNAs. Overall, our analysis demonstrated that lncRNAs are transcribed alongside mRNAs in various biological contexts. Given their prevalence in the transcriptome, incorporating lncRNAs into transcriptome analyses will enhance our understanding of their functions, shedding light on their regulatory roles in An. gambiae biology.

molecular biology↗

bioRxiv2024

Exploring the Correlation Between UVB Sensitivity and SLE Activity: Insights into UVB-Driven Pathogenesis in Lupus Erythematosus

Lupus erythematosus (LE) comprises various autoimmune inflammatory diseases, with significant overlap between cutaneous LE (CLE) and systemic LE (SLE). A key feature of both CLE and SLE is UV photosensitivity, particularly in UV-exposure-related skin inflammation. Despite this, reliable and objective UVB photosensitivity indicators closely correlating with LE activity have yet to be identified, and the underlying cellular and molecular mechanisms linking UVB sensitivity with LE onset and progression remain unclear. We discovered that ultraviolet B minimal erythema dose (UVB-MED), a quantitative photosensitivity measure, is a significant and independent risk factor for SLE activity, demonstrating a negative correlation with SLEDAI (r = -0.58, P < 0.0001). Comprehensive transcriptomic analyses of large-scale CLE and SLE samples revealed more pronounced and extensive UVB-response gene dysregulation in skin tissues compared to blood. Additionally, 14 lupus activity-correlated, UVB-response genes (UVBACGs) were identified, including eight interferon-stimulated genes (IRF7, ISG20, ISG15, IFI44, IFITM1, MX1, LY6E, OASL) and others (JUN, PTTG1, HLA-F, CAV1, HOPX, RPL3), with dysregulation evident in both skin and blood cells, particularly immunocytes. Conventional LE therapies were found to be associated with these genes and may potentially regulate them, thereby contributing to therapeutic effects. These findings highlight the role of UVB in triggering autoimmune inflammation in the skin, which may subsequently spread to systemic inflammation via immune cells and factors. UVBACGs play a critical role in this process and may serve as targets for precise LE therapies, providing insight into the link between UVB photosensitivity and LE progression.

immunology↗

bioRxiv2024

Regulation of tmTNF-α Processing by FRMD8 in Triple-Negative Breast Cancer Metastasis: Insights into Molecular Pathway Dynamics

PurposeBreast cancer remains the leading cause of cancer-related mortality among women worldwide, with late-stage diagnoses prevalent in China resulting in significantly lower survival rates. This study focuses on identifying genes implicated in breast cancer metastasis, highlighting the role of Tumor Necrosis Factor-alpha (TNF-) and its forms--transmembrane (tmTNF-) and soluble (sTNF-). Experimental DesignTNF- is crucial for activating NF-{kappa}B pathways that regulate genes involved in cell adhesion, migration, and immune evasion, all essential for cancer metastasis. We conducted comprehensive analyses of FRMD8, a member of the FERM domain-containing proteins, as a significant regulator of tmTNF-. Through integrative multi-omics and cellular functional studies, the relationship between FRMD8, iRhom2, and ADAM17 was assessed in the context of breast cancer metastasis. ResultsOur findings reveal that FRMD8 forms a complex with iRhom2 and ADAM17, enhancing the stability and sheddase activity of ADAM17, which is vital for the release of TNF-. The absence of FRMD8 leads to decreased ADAM17 activity, increasing the availability of tmTNF- and potentially promoting metastasis. This effect suggests that FRMD8 is a key modulator of TNF- processing. ConclusionsThis study explores how FRMD8 influences TNF- processing and the metastatic behavior of breast cancer, providing insights into molecular dynamics that could guide future therapeutic strategies to improve outcomes in breast cancer patients.

cancer biology↗

bioRxiv2024

Learning-Augmented Sketching Offers Improved Performance for Privacy Preserving and Secure GWAS

The introduction of trusted execution environments (TEEs), such as secure enclaves provided by the Intel SGX technology has enabled secure and privacy-preserving computation on the cloud. The stringent resource limitations, such as memory constraints, required by some TEEs necessitates the development of computational approaches with reduced memory usage, such as sketching. One example is the SkSES method for GWAS on a cohort of case and control samples from multiple institutions, which identifies the most significant SNPs in a privacy-preserving manner without disclosing sensitive genotype information to other institutions or the cloud service provider. Here we show how to improve the performance of SkSES on large datasets by augmenting it with a learning-augmented approach. Specifically, we show how individual institutions can perform smaller scale GWAS on their own datasets and identify two sets of variants according to certain criteria, which are then used to guide the sketching process to more accurately identify significant variants over the collective dataset. The new method achieves up to 40% accuracy gain compared to the original SkSES method under the same memory constraints on datasets we tested on. The code is available at https://github.com/alreadydone/sgx-genome-variants-search. Contactcenk.sahinalp@nih.gov

bioinformatics↗

bioRxiv2024

Involvement of 5' and 3' UTRs on SARS-CoV-2 Genome Packaging

The SARS-CoV-2 virus, responsible for the COVID-19 pandemic, packages its large single-stranded RNA genome through a precise yet enigmatic mechanism. A packaging signal (PS) within its genome was proposed to facilitate the assembly of new viral particles. Here in this study, we report the role of the 5 and 3 untranslated regions (UTRs) in PS-mediated genome packaging. Utilizing proximity ligation data, we demonstrate direct interactions between the UTRs and the PS9 element, a key packaging signal within the SARS-CoV-2 genome. Multiple evidence confirmed that the presence of UTRs enhance the packaging efficiency of infectious virus-like particles (iVLPs) and recruits more nucleocapsid (N) protein, suggesting a critical role in genome compaction and packaging. These insights into the regulatory mechanisms of SARS-CoV-2 genome packaging provide novel targets for antiviral therapeutics and contribute to the broader understanding of coronavirus assembly.

microbiology↗

bioRxiv2024

Shade Inhibits Cambial Activity in Populus Stems by the SPL16/SPL23-Mediated Cytokinin Pathway

Trees in natural forests or plantations often encounter neighbor proximity signal that negatively impacts wood production. However, the molecular basis underlying shade-regulation of vascular cambial activity during stem radial growth remains unknown in woody species. Here, we revealed that high stand density and simulated shade (low R/FR ratio) suppress the division and differentiation of cambial cells in poplar stems. A genome-wide screen for Populus SQUAMOSA PROMOTER BINDING PROTEIN-LIKE (SPL) genes identified that SPL16 and SPL23 are preferentially expressed in the phloem and cambium, being downregulated by simulated shade. Knocking out SPL16/23 impaired cambial activity, whereas phloem-specific overexpression of SPL16 stimulated cambial proliferation and mitigated the shade-inhibition of cambial activity. Additionally, shade decreased bioactive cytokinin (CK) levels by suppressing the expression of CK biosynthesis genes IPT5a, IPT5b and LOG1b in poplar stems. Molecular and genetic studies reveled that SPL16/23 directly activate IPT5s/LOG1b expression to promote CK biosynthesis and cambial activity. Moreover, elevated miR156 expression in shade-treated stems regulated SPL16/23 at the post-transcriptional level, mediating shades effects on cambial activity. Collectively, our findings unravel that the miR156-SPL16/23-IPT5/LOG1-cytokinin pathway operates in the shade-mediated inhibition of cambial activity, providing potential targets for the genetic improvement of shade-tolerant trees.

plant biology↗

bioRxiv2024

An integrated view of the structure and function of the human 4D nucleome

The dynamic three-dimensional (3D) organization of the human genome (the "4D Nucleome") is closely linked to genome function. Here, we integrate a wide variety of genomic data generated by the 4D Nucleome Project to provide a detailed view of human 3D genome organization in widely used embryonic stem cells (H1-hESCs) and immortalized fibroblasts (HFFc6). We provide extensive benchmarking of 3D genome mapping assays and integrate these diverse datasets to annotate spatial genomic features across scales. The data reveal a rich complexity of chromatin domains and their sub-nuclear positions, and over one hundred thousand structural loops and promoter-enhancer interactions. We developed 3D models of population-based and individual cell-to-cell variation in genome structure, establishing connections between chromosome folding, nuclear organization, chromatin looping, gene transcription, and DNA replication. We demonstrate the use of computational methods to predict genome folding from DNA sequence, uncovering potential effects of genetic variants on genome structure and function. Together, this comprehensive analysis contributes insights into human genome organization and enhances our understanding of connections between the regulation of genome function and 3D genome organization in general.

genomics↗

bioRxiv2024

Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of Type 1 Diabetes

Aims/hypothesisSurviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death-1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesized that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. MethodsBeta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry, and ELISA. EV PD-L1: PD-1 binding was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8 T cells. Plasma EV and soluble PD-L1 were assayed in plasma of individuals with islet autoantibody positivity (Ab+) or recent-onset type 1 diabetes and compared to non-diabetic controls. ResultsPD-L1 protein colocalized with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. 24-h IFN- or IFN-{square} treatment induced a two-fold increase in EV PD-L1 cargo without a corresponding increase in number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8 T cells. Plasma EV PD-L1 levels were increased in islet Ab+ individuals, particularly in those with single Ab+, Additionally, in from individuals with either Ab+ or type 1 diabetes, but not in controls, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV-PD-L1 could be protective for residual beta cell function. Conclusions/interpretationIFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8 T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in islet autoantibody positive patients compared to controls. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death. Research in contextO_ST_ABSWhat is already known about this subject? (maximum of 3 bullet points)C_ST_ABSO_LIExtracellular vesicles (EVs) serve as paracrine effectors in the islet microenvironment in health and disease. C_LIO_LIInterferon-alpha (IFN-) and IFN-gamma (IFN-{square}) are key cytokines contributing to type 1 diabetes pathophysiology and islet IFN signalling increases beta cell programmed death-ligand 1 (PD-L1) expression. C_LIO_LIUp-regulation of beta cell PD-L1 in the non-obese diabetic (NOD) mouse model delays progression of type 1 diabetes. C_LI What is the key question? (one bullet point only; formatted as a question)O_LIDo beta cells exposed to IFNs upregulate EV PD-L1 and can these changes be detected in circulation? C_LI What are the new findings? (maximum of 3 bullet points)O_LIIFN- or IFN-{square} exposure increases beta cell EV PD-L1 cargo in beta cell lines and human islets. C_LIO_LIPD-L1 is present on the surface of beta cell EVs, binds PD-1 and EV PD-L1 inhibits proliferation, activation and cytotoxicity of murine CD8 T cells. C_LIO_LIEV PD-L1 levels are higher in islet autoantibody positive individuals compared to nondiabetic controls and levels of circulating EV PD-L1 positively correlate with residual beta cell function in islet autoantibody positive individuals as well as in individuals with recent-onset type 1 diabetes. C_LI How might this impact on clinical practice in the foreseeable future? (one bullet point only)O_LIA beneficial effect of PD-L1+ EVs could ultimately be harnessed as an intervention to prevent autoimmune beta cell destruction. Circulating EV PD-L1 cargo has potential as a minimally invasive and informative biomarker to offer insights into the pathogenesis and progression of type 1 diabetes. C_LI

cell biology↗

bioRxiv2024

The H3K4me3 binding ALFIN-LIKE proteins recruit SWR1 for gene-body deposition of H2A.Z

The H2A.Z histone variant is highly enriched over gene bodies, playing an essential role in several genome-templated processes, including transcriptional regulation and epigenetic patterning across eukaryotes. The SWR1 chromatin remodeling complex deposits H2A.Z. How SWR1 is directed to gene bodies is largely unknown. Here, we show that ALFIN-LIKE (AL) proteins are responsible for H2A.Z gene body patterning in Arabidopsis. AL proteins encode H3K4me3-binding PHD domains, and by ChIP-seq, we confirm preferential binding of AL5 to H3K4me3 over H3K4me1/2 in planta. We observe a global reduction in H2A.Z in al septuple mutants (al7m), especially of over H3K4me3-enriched genic regions. While MBD9 recruits SWR1 to nucleosome-free regions, ALs act non-redundantly with MBD9 for deposition of H2A.Z. Notably, al7m mutants show severe developmental abnormalities and upregulation of H2A.Z gene body-enriched responsive genes. Therefore, we propose a model whereby AL proteins direct gene body enrichment of H2A.Z by recruiting SWR1 to H3K4me3-containing responsive genes.

plant biology↗

bioRxiv2024

Auditory Cortex Learns to Discriminate Audiovisual Cues through Selective Multisensory Enhancement

Multisensory object discrimination is essential in everyday life, yet the neural mechanisms underlying this process remain unclear. In this study, we trained rats to perform a two-alternative forced-choice task using both auditory and visual cues. Our findings reveal that multisensory perceptual learning actively engages auditory cortex (AC) neurons in both visual and audiovisual processing. Importantly, many audiovisual neurons in the AC exhibited experience-dependent associations between their visual and auditory preferences, displaying a unique integration model. This model employed selective multisensory enhancement for the auditory-visual pairing guiding the contralateral choice, which correlated with improved multisensory discrimination. Furthermore, AC neurons effectively distinguished whether a preferred auditory stimulus was paired with its associated visual stimulus using this distinct integrative mechanism. Our results highlight the capability of sensory cortices to develop sophisticated integrative strategies, adapting to task demands to enhance multisensory discrimination abilities.

neuroscience↗