Biology subjects

Xuan, Z.

Publications and source records attributed to Xuan, Z..

15 recordsLinked to original sources

bioRxiv2026

miR-34/449 miRNAs regulate choroid plexus ciliogenesis to control cerebrospinal fluid production

A developmental increase in cerebrospinal fluid (CSF) production during development is essential for neuronal growth and ventricular expansion. A key regulator of CSF production is the specialized sensory multicilia of the choroid plexus (ChP), which mediate non-canonical Sonic hedgehog (Shh) signaling to suppress water channel and ion transporter expression, thereby limiting CSF production. ChP multicilia progressively shortens during development, attenuating Shh signaling and promoting CSF production. Here, we identify miR-34/449 miRNAs as essential regulators of ChP multiciliogenesis. Whereas mutations in canonical ciliogenesis genes elevate CSF production and contribute to hydrocephaly, deletion of miR-34/449 reduces CSF volume and causes microcephaly. Loss of miR-34/449 miRNAs causes excessive basal body amplification, defective basal body docking, and failure of developmental multiciliary shortening. Consequently, miR-34/449-deficient ChP cilia remain abnormally long and fail to attenuate Shh signaling, resulting in sustained repression of water channel and ion transporter expression and reduced CSF production. Mechanistically, miR-34/449 miRNAs directly target Gmnc, a master transcriptional regulator of multiciliogenesis, to restrain basal body amplification and promote basal body docking. Together, our findings identify miR-34/449 miRNAs as critical regulators of ChP multiciliogenesis and establish the developmental remodeling of ChP multicilia as a mechanism to couple Shh signaling dynamics to developmental control of CSF production.

developmental biology↗

bioRxiv2026

GMIP-PLSR: A Nextflow Pipeline for GWAS and Multi-Omics Integration in Gene Prioritization Using PLSR

Genome-wide association studies (GWAS) have significantly advanced our understanding of complex traits and diseases, but their interpretive power remains limited due to challenges in identifying causal genes and pathways. Integrating GWAS with multi-omics data--such as gene expression, protein-protein interactions, and gene-pathway networks have the potential to enhance biological insights and improve gene prioritization. To fulfill this potential and need, we developed the GWAS & Multi-omics Integration Pipeline (GMIP), a flexible and scalable framework that incorporates widely used tools such as PoPS, MAGMA, and benchmarker to enrich GWAS findings. However, PoPS suffers from multicollinearity in its features, which can impact performance. To overcome this, we introduce GMIP-PLSR, an extension of GMIP that uses Partial Least Squares Regression (PLSR) to manage multicollinearity effectively. We applied GMIP-PLSR across multiple GWAS datasets, demonstrating superior performance over PoPS in most cases. In a case study on NAFLD, GMIP-PLSR, using features derived from both disease-specific scRNA-seq and general PoPS features, identified gene sets with higher heritability and stronger enrichment in known NAFLD pathways, confirming its ability to enhance GWAS findings. Built on Nextflow, GMIP is computationally efficient, adaptable to diverse research environments, and provides a robust solution for gene reprioritization in post-GWAS analyses. GMIP-PLSR is available at https://github.com/mohammedmsk/GMIP.

bioinformatics↗

bioRxiv2025

Hi-GREx: A 3D Genome Guided Framework for enhancing Gene Expression Prediction Using Hi-C Selected Distal SNPs

Genome-Wide Association Study (GWAS) method has been successfully used to map thousands of loci associated with complex traits, but its ability to reveal the molecular mechanisms altered in complex diseases has been limited due to not including combinations and interactions between markers when predicting a disease. Transcriptome-Wide Association Studies (TWAS) estimate the aggregate effects of multiple genetic variants on complex diseases and represent a promising approach to address the limitations of GWAS. In particular, TWAS provides insights into the functional consequences of disease-associated SNPs by linking them to gene transcription, thereby offering a mechanistic understanding that GWAS alone cannot provide. However, TWAS associated variants have been annotated with the closest or most biologically relevant candidate gene within arbitrarily defined distances but fails to account for long distance SNPs which can affect many genes and have a widespread impact on regulatory networks. Therefore, there is a need to leverage these observed enrichments and build a method that incorporates both short and long distance-associations between SNPs and complex phenotypes. Here we present a method which can utilize Hi-C data to capture "informative" long-distance SNPs and aim to improve prediction accuracy of previous TWAS method. We benchmarked our method on GTEx brain cortex genotype and expression data together with the corresponding Hi-C data. By using the "informative" long distance SNPs selected based on Hi-C, our method improved prediction accuracy of gene expression for 77.4% of the active genes across the entire genome. Particularly, our method can build significant expression models for 18% of genes which were missed by using only short-distance SNPs. Our method has demonstrated the efficiency and importance of utilizing long-distance SNPs in predicting gene expression and can further enhance the power of TWAS methods.

bioinformatics↗

bioRxiv2025

Multicilia dynamically transduce Shh signaling to regulate choroid plexus functions

Choroid plexus is a major site for cerebrospinal fluid (CSF) production, characterized by a multiciliated epithelial monolayer that regulates CSF production. We demonstrate that defective choroid plexus ciliogenesis or Intraflagellar transport yields neonatal hydrocephalus, at least in part, due to increased water channel Aqp1 and ion transporter Atp1a2 expression. We demonstrate choroid plexus multicilia as sensory cilia, transducing both canonical and non-canonical Shh signaling. Interestingly, it is the non-canonical Shh signaling that represses Aqp1 and Atp1a2 expression by Smo/Gi/cAMP pathway. Choroid plexus multicilia exhibit unique ciliary ultrastructure, carrying features of both primary and motile cilia. Unlike most cilia that elongate during maturation, choroid plexus ciliary length decreases during development, causing a decline of Shh signaling intensity in developing choroid plexus, a derepression of Aqp1 and Atp1a2, and ultimately, an increased CSF production. Hence, developmental dynamics of choroid plexus multicilia dampens the Shh signaling intensity to promote CSF production.

developmental biology↗

bioRxiv2023

Obesity modifies cell fate plasticity of Pdgfrα-expressing mammary adipocyte progenitors to promote an aberrant mammary microenvironment

Excess fat gain culminating in obesity is a mounting global pandemic associated with a myriad of diseases including a higher risk of developing multiple cancers such as breast cancer. The underlying biological basis for obesity-linked breast cancer is attributed to alterations in adipose tissue-derived endocrine, metabolic and inflammatory factors. However, the precise cell types responsible for generating a cancer-susceptible mammary gland in obesity are not well understood. Using diet-induced obesity in conjunction with genetic reporter mouse models, we reveal elevated mammary adipocyte progenitors (MAPs) expressing Platelet-Derived Growth Factor Receptor alpha (PDGFR) in the mammary tissue microenvironment during obesity. Single-cell RNA sequencing analysis demonstrate intensified obesity-driven trajectories of MAPs to immune and epithelial progenitor cells. Further, lineage tracing indicates an invasive cellular state of MAPs that confers greater access of MAP descendants into the mammary epithelium concomitant with their transition into immune and epithelial cell fates. MAPs in obesity exhibit heightened activation of cancer-associated and inflammatory pathways where Egfr is identified as a common target upregulated in MAPs. Mechanistic studies on purified MAPs with a major obesity diet component and EGFR stimulation corroborate dynamic EGFR-mediated MAP responses. Our findings uncover MAPs as key contributors to forging an aberrant mammary gland in obesity, providing insight into the potential utility of targeting this cell lineage for eradicating cancer risk related to augmented adiposity.

cell biology↗

bioRxiv2022

Conserved Untranslated Regions of Multipartite Viruses: Natural Markers of Novel Viral Genomic Components and Tags of Viral Evolution

Viruses with split genomes are categorized as being either segmented or multipartite according to whether their genomic segments occur in single or different virions. Some complexity will exist, in that inherited "core" vital segments viruses may renew the others once host and environmental alterations keep driving viral evolution. Despite this uncertainty, empirical observations have been made across the split genomes in the untranslated regions (UTRs) on the short or long stretches of conserved or identical sequences. In this study, we describe a methodology that combines RNA and small RNA sequencing, conventional BLASTx, and iterative BLASTn of UTRs to detect viral genomic components even if they encode orphan genes (ORFans). Within the phylum Kitrinoviricota, novel putative multipartite viruses and viral genomic components were annotated using data obtained from our sampling or publicly available sources. The novel viruses, as extensions or intermediate nodes, enriched the information of the evolutionary networks. Furthermore, the diversity of novel genomic components emphasized the evolutionary roles of reassortment and recombination, as well as genetic deletion, strongly supporting the genomic complexity. These data also suggest insufficient knowledge of these genomic components for categorizing some extant viral taxa. The relative conservation of UTRs at the genome level may explain the relationships between monopartite and multipartite viruses and how the multipartite viruses can have a life strategy involving multiple host cells. Author summaryThe current workflows for virus identification are largely based on high-throughput sequencing and coupled protein sequence homology-dependent analysis methods and tools. However, for viruses with split genomes, the identification of genomic components whose deduced protein sequences are not homologous to known sequences is inadequate. Furthermore, many plant-infecting multipartite viruses contain conserved UTRs across their genomic components. Based on this, we propose a practical method of UTR-backed iterative BLASTn (UTR-iBLASTn) to explore the components with ORFans and study virus evolution using the UTRs as signals. These shed light on viral "dark matter"--unknown/omitted genomic components of segmented/multipartite viruses from different kingdoms and hosts, and the origins of these components.

microbiology↗

bioRxiv2021

A Novel Oncogenic Function of PRC2 Heterogeneity in Medulloblastoma

Intratumor epigenetic heterogeneity is emerging as a key mechanism underlying tumor evolution and drug resistance. Medulloblastomas, the most common childhood malignant brain tumor, are classified into four subtypes including SHH medulloblastomas, which are characterized by elevated SHH signaling and a cerebellum granule neuron precursor (CGNP) cell-of-origin. Medulloblastomas are highly associated with epigenetic abnormalities. We observed that the histone H3K27 methyltransferase polycomb repressor complex 2 (PRC2) is often heterogeneous within individual SHH medulloblastoma tumors. Using mouse models, we showed that while a complete deletion of the PRC2 core subunit EED inhibited medulloblastoma growth, a mosaic deletion of EED significantly enhanced tumor growth. EED is intrinsically required for CGNP maintenance by inhibiting both neural differentiation and cell death. Complete EED deletion led to CGNP depletion and reduced occurrence of medulloblastoma. Surprisingly, we found that medulloblastomas with mosaic EED levels grew faster than did control wildtype tumors and expressed increased levels of oncogenes such as Igf2. Igf2 is directly repressed by PRC2 and has been demonstrated to be both necessary and sufficient for SHH medulloblastoma progression. We showed that IGF2 mediated the oncogenic effects of PRC2 heterogeneity in tumor growth. Using a human medulloblastoma cell line, we generated clones with different EED levels and confirmed that EEDlow cells could stimulate the growth of EEDhigh cells through derepressed IGF2 signals. Thus, PRC2 heterogeneity controls medulloblastoma growth through both intrinsic growth competence and non-cell autonomous mechanisms in distinct tumor subclones. We reveal a novel oncogenic function of PRC2 heterogeneity in tumor development.

cancer biology↗

bioRxiv2021

The active zone protein Clarinet regulates ATG-9 trafficking at synapses and presynaptic autophagy

In neurons, autophagy is temporally and spatially regulated to occur near presynaptic sites. How trafficking of autophagy proteins is regulated to support synaptic autophagy is not well understood. From forward genetic screens, we identify a role for the long isoform of the active zone protein Clarinet (CLA-1L) in regulating trafficking of autophagy protein ATG-9 at synapses, and presynaptic autophagy. ATG-9 is a transmembrane protein that undergoes activity-dependent exo-endocytosis at synapses, and mutations in CLA-1L result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates. CLA-1L extends from the active zone to the periactive zone, and genetically interacts with periactive zone proteins required for clathrin-dependent endocytosis. We find that CLA-1L is specifically required for sorting of ATG-9 at synapses, likely via endosome-mediated endocytosis, and for activity-dependent presynaptic autophagy. Our findings provide mechanistic insights into how active zone proteins regulate key steps of ATG-9 exo-endocytosis, a process that could couple the activity state of the neuron and autophagy. HighlightsO_LI* The long isoform of the active zone protein Clarinet (CLA-1L) regulates ATG-9 trafficking at synapses C_LIO_LI* CLA-1L extends from the active zone to the periactive zone and cooperates with the periactive zone endocytic proteins EHS-1/EPS15 and ITSN-1/ intersectin 1 in ATG-9 trafficking during exo-endocytosis C_LIO_LI* Mutations in CLA-1L, or in clathrin-associated adaptor molecules, result in abnormal accumulation of ATG-9 into clathrin-rich endocytic intermediates C_LIO_LI* CLA-1L mutants which affect ATG-9 trafficking are also defective in activity-dependent presynaptic autophagy C_LI

neuroscience↗

bioRxiv2021

Klf5 establishes bi-potential cell fate by dual regulation of ICM and TE specification genes

Early blastomeres of mouse preimplantation embryos exhibit bi-potential cell fate, capable of generating both embryonic and extra-embryonic lineages in blastocysts. Here, we identified three major 2 cell (2C) specific endogenous retroviruses (ERVs) as the molecular hallmark of the bi-potential plasticity. Using the LTRs of all three 2C-ERVs, we identified Klf5 as their major upstream regulator. Klf5 is essential for bi-potential cell fate: a single Klf5-overexpressing ESC generated terminally differentiated embryonic and extra-embryonic lineages in chimeric embryos, and Klf5 directly induces both ICM and TE specification genes. Intriguingly, Klf5 and Klf4 act redundantly during ICM specification, whereas Klf5 deficiency alone impairs TE specification. Klf5 is regulated by multiple 2C-specific transcription factors, particularly Dux, and the Dux/Klf5 axis is evolutionarily conserved. Altogether, the 2C-specific transcription program converges on Klf5 to establish bi-potential cell fate, enabling a cell state with dual activation of ICM and TE genes.

developmental biology↗

bioRxiv2021

A species-specific retrotransposon drives a conserved Cdk2ap1 isoform essential for preimplantation development

Retrotransposons mediate gene regulation in multiple developmental and pathological processes. Here, we characterized the transient retrotransposon induction in preimplantation development of eight mammalian species. While species-specific in sequences, induced retrotransposons exhibit a similar preimplantation profile, conferring gene regulatory activities particularly through LTR retrotransposon promoters. We investigated a mouse-specific MT2B2 retrotransposon promoter, which generates an N-terminally truncated, preimplantation-specific Cdk2ap1{Delta}N isoform to promote cell proliferation. Cdk2ap1{Delta}N functionally contrasts to the canonical Cdk2ap1, which represses cell proliferation and peaks in mid-gestation stage. The mouse-specific MT2B2 element is developmentally essential, as its deletion abolishes Cdk2ap1{Delta}N, reduces cell proliferation and impairs embryo implantation. Intriguingly, Cdk2ap1{Delta}N is evolutionarily conserved across mammals, driven by species-specific promoters. The distinct preimplantation Cdk2ap1{Delta}N expression across different mammalian species correlates with their different duration in preimplantation development. Hence, species-specific transposon promoters can yield evolutionarily conserved, alternative protein isoforms, bestowing them with new functions and species-specific expression to govern essential biological divergence. One Sentence SummaryIn mammalian preimplantation embryos, retrotransposon promoters generate conserved gene isoforms, confer species-specific expression, and perform essential developmental functions.

developmental biology↗

bioRxiv2020

Presynaptic autophagy is coupled to the synaptic vesicle cycle via ATG-9

Autophagy is a cellular degradation pathway essential for neuronal health and function. Autophagosome biogenesis occurs at synapses, is locally regulated and increases in response to neuronal activity. The mechanisms that couple autophagosome biogenesis to synaptic activity remain unknown. In this study we determine that trafficking of ATG-9, the only transmembrane protein in the core autophagy pathway, links the synaptic vesicle cycle with autophagy. ATG-9 positive vesicles in C. elegans are generated from the trans-Golgi network via AP3-dependent budding, and delivered to presynaptic sites. At presynaptic sites, ATG-9 undergoes exo-endocytosis in an activity-dependent manner. Mutations that disrupt endocytosis, including one associated with Parkinsons disease, result in abnormal ATG-9 accumulation at clathrin-rich synaptic foci and defects in activity-dependent presynaptic autophagy. Our findings uncover regulated key steps of ATG-9 trafficking at presynaptic sites, and provide evidence that ATG-9 exo-endocytosis couples autophagosome biogenesis at presynaptic sites with the activity-dependent synaptic vesicle cycle. HighlightsO_LIIn C. elegans, ATG-9 is delivered to presynaptic sites in vesicles generated from the trans-Golgi network via AP-3-dependent budding C_LIO_LIATG-9 vesicles undergo activity-dependent exo-endocytosis at presynaptic sites C_LIO_LIMutations in endocytic proteins, including a mutation associated with Parkinsons disease, result in abnormal ATG-9 accumulation at clathrin-rich foci C_LIO_LIAbnormal accumulation of ATG-9 at clathrin-rich foci is associated with defects in activity-dependent presynaptic autophagy C_LI

neuroscience↗

bioRxiv2020

Neuronal Activity-Induced BRG1 Phosphorylation Regulates Enhancer Activation

Neuronal activity-induced enhancers drive the gene induction in response to stimulation. Here, we demonstrate that BRG1, the core subunit of SWI/SNF-like BAF ATP-dependent chromatin remodeling complexes, regulates neuronal activity-induced enhancers. Upon stimulation, BRG1 is recruited to enhancers in an H3K27Ac-dependent manner. BRG1 regulates enhancer basal activities and inducibility by affecting cohesin binding, enhancer-promoter looping, RNA polymerase II recruitment, and enhancer RNA expression. Furthermore, we identified a serine phosphorylation site in BRG1 that is induced by neuronal activities and is sensitive to CaMKII inhibition. BRG1 phosphorylation affects its interaction with several transcription co-factors, possibly modulating BRG1 mediated transcription outcomes. Using mice with knock-in mutations, we showed that non-phosphorylatable BRG1 fails to efficiently induce activity-dependent genes, whereas phosphomimic BRG1 increases the enhancer activities and inducibility. These mutant mice displayed anxiety-like phenotypes and altered responses to stress. Therefore, our data reveal a mechanism connecting neuronal signaling to enhancer activities through BRG1 phosphorylation.

molecular biology↗

bioRxiv2019

G-Quadruplexes Act as Sequence Dependent Chaperones via Protein Oligomerization

Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent aggregation up to 300-fold more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences effects on aggregation, we demonstrate that the holdase chaperone effect of nucleic acids is highly sequence dependent. Quadruplexes are found to have especially potent effects on aggregation with many different proteins via quadruplex:protein oligomerization. These observations contextualize recent reports of quadruplexes playing important roles in aggregation-related diseases, such as Fragile X and Amyotrophic lateral sclerosis (ALS).

biochemistry↗

bioRxiv2019

The Glycolytic Protein Phosphofructokinase Dynamically Relocalizes into Subcellular Compartments with Liquid-like Properties in vivo

While much is known about the biochemical regulation of glycolytic enzymes, less is understood about how they are organized inside cells. Here we built a hybrid microfluidic-hydrogel device for use in Caenorhabditis elegans to systematically examine and quantify the dynamic subcellular localization of the rate-limiting enzyme of glycolysis, phosphofructokinase-1/PFK-1.1. We determine that endogenous PFK-1.1 localizes to distinct, tissue-specific subcellular compartments in vivo. In neurons, PFK-1.1 is diffusely localized in the cytosol, but capable of dynamically forming phase-separated condensates near synapses in response to energy stress from transient hypoxia. Restoring animals to normoxic conditions results in the dispersion of PFK-1.1 in the cytosol, indicating that PFK-1.1 reversibly organizes into biomolecular condensates in response to cues within the cellular environment. PFK-1.1 condensates exhibit liquid-like properties, including spheroid shapes due to surface tension, fluidity due to deformations, and fast internal molecular rearrangements. Prolonged conditions of energy stress during sustained hypoxia alter the biophysical properties of PFK-1.1 in vivo, affecting its viscosity and mobility within phase-separated condensates. PFK-1.1s ability to form tetramers is critical for its capacity to form condensates in vivo, and heterologous self-association domain such as cryptochrome 2 (CRY2) is sufficient to constitutively induce the formation of PFK-1.1 condensates. PFK-1.1 condensates do not correspond to stress granules and might represent novel metabolic subcompartments. Our studies indicate that glycolytic protein PFK-1.1 can dynamically compartmentalize in vivo to specific subcellular compartments in response to acute energy stress via multivalency as phase-separated condensates.

cell biology↗

bioRxiv2017

Clarinet (CLA-1), a novel active zone protein required for synaptic vesicle clustering and release

Active zone proteins cluster synaptic vesicles at presynaptic terminals and coordinate their release. In forward genetic screens we isolated a novel C. elegans active zone gene, clarinet (cla-1). cla-1 mutants exhibit defects in synaptic vesicle clustering, reduced spontaneous neurotransmitter release, increased synaptic depression and reduced synapse number. Ultrastructurally, cla-1 mutants have fewer synaptic vesicles adjacent to the dense projection and an increased number of docked vesicles. Cla-1 encodes 3 isoforms containing common C-terminal PDZ and C2 domains with homology to vertebrate active zone proteins Piccolo and RIM. The short isoform localizes exclusively to the active zone while a longer ~9000 amino acid isoform colocalizes with synaptic vesicles. Specific loss of CLA-1L results in synaptic vesicle clustering defects and increased synaptic depression, but not in reduced synapse number or mini frequency. Together our data indicate that specific isoforms of clarinet serve distinct functions, regulating synapse development, synaptic vesicle clustering and release.

neuroscience↗