Biology subjects

Han, Y.

Publications and source records attributed to Han, Y..

At least 145 records · Page 8Linked to original sources

bioRxiv2024

Adipogenin Dictates Adipose Tissue Expansion by Facilitating the Assembly of a Dodecameric Seipin Complex

Adipogenin (Adig) is an evolutionarily conserved microprotein and is highly expressed in adipose tissues and testis. Here, we identify Adig as a critical regulator for lipid droplet formation in adipocytes. We determine that Adig interacts directly with seipin, leading to the formation of a rigid complex. We solve the structure of the seipin/Adig complex by Cryo-EM at 2.98[A] overall resolution. Surprisingly, seipin can form two unique oligomers, undecamers and dodecamers. Adig selectively binds to the dodecameric seipin complex. We further find that Adig promotes seipin assembly by stabilizing and bridging adjacent seipin subunits. Functionally, Adig plays a key role in generating lipid droplets in adipocytes. In mice, inducible overexpression of Adig in adipocytes substantially increases fat mass, with enlarged lipid droplets. It also elevates thermogenesis during cold exposure. In contrast, inducible adipocyte-specific Adig knockout mice manifest aberrant lipid droplet formation in brown adipose tissues and impaired cold tolerance.

cell biology↗

bioRxiv2024

HIV-1-envelope trimer transitions from prefusion-closed to CD4-bound-open conformations through an occluded-intermediate state

HIV-1 infection is initiated by the interaction between the gp120 subunit in the envelope (Env) trimer and the cellular receptor CD4 on host cells. This interaction induces substantial structural rearrangement of the Env trimer. Currently, static structural information for prefusion-closed trimers, CD4-bound prefusion-open trimers, and various antibody-bound trimers is available. However, dynamic features between these static states (e.g., transition structures) are not well understood. Here, we investigate the full transition pathway of a site specifically glycosylated Env trimer between prefusion-closed and CD4-bound-open conformations by collective molecular dynamics and single-molecule Forster resonance energy transfer (smFRET). Our investigations reveal and confirm important features of the transition pathway, including movement of variable loops to generate a glycan hole at the trimer apex and formation or rearrangements of -helices and {beta}-strands. Notably, by comparing the transition pathway to known Env-structures, we uncover evidence for a transition intermediate, with four antibodies, Ab1303, Ab1573, b12, and DH851.3, recognizing this intermediate. Each of these four antibodies induce population shifts of Env to occupy a newly observed smFRET state: the "occluded-intermediate" state. We propose this occluded-intermediate state to be both a prevalent state of Env and an on-path conformation between prefusion-closed and CD4-bound-open states, previously overlooked in smFRET analyses.

bioinformatics↗

bioRxiv2024

TRPML1 gating modulation by allosteric mutations and lipids

Transient Receptor Potential Mucolipin 1 (TRPML1) is a lysosomal cation channel whose loss-of-function mutations directly cause the lysosomal storage disorder mucolipidosis type IV (MLIV). TRPML1 can be allosterically regulated by various ligands including natural lipids and small synthetic molecules and the channel undergoes a global movement propagated from ligand-induced local conformational changes upon activation. In this study, we identified a functionally critical residue, Tyr404, at the C-terminus of the S4 helix, whose mutations to tryptophan and alanine yield gain- and loss-of-function channels, respectively. These allosteric mutations mimic the ligand activation or inhibition of the TRPML1 channel without interfering with ligand binding and both mutant channels are susceptible to agonist or antagonist modulation, making them better targets for screening potent TRPML1 activators and inhibitors. We also determined the high-resolution structure of TRPML1 in complex with the PI(4,5)P2 inhibitor, revealing the structural basis underlying this lipid inhibition. In addition, an endogenous phospholipid likely from sphingomyelin is identified in the PI(4,5)P2-bound TRPML1 structure at the same hotspot for agonists and antagonists, providing a plausible structural explanation for the inhibitory effect of sphingomyelin on agonist activation.

biophysics↗

bioRxiv2024

SMARCA4 mutation induces tumor cell-intrinsic defects in enhancer landscape and resistance to immunotherapy

Cancer genomic studies have identified frequent alterations in components of the SWI/SNF (SWItch/Sucrose Non- Fermenting) chromatin remodeling complex including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. However, the mechanistic basis of immunotherapy resistance is unknown. Here, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, we show that SMARCA4 loss caused decreased response to anti-PD1 immunotherapy associated with significantly reduced infiltration of dendritic cells (DCs) and CD4+ T cells into the tumor microenvironment (TME). Mechanistically, we show that SMARCA4 loss in tumor cells led to profound downregulation of STING, IL1{beta} and other components of the innate immune system as well as inflammatory cytokines that are required for efficient recruitment and activity of immune cells. We establish that this deregulation of gene expression is caused by cancer cell-intrinsic reprogramming of the enhancer landscape with marked loss of chromatin accessibility at enhancers of genes involved in innate immune response such as STING, IL1{beta}, type I IFN and inflammatory cytokines. Interestingly, we observed that transcription factor NF-{kappa}B binding motif was highly enriched in enhancers that lose accessibility upon SMARCA4 deficiency. Finally, we confirmed that SMARCA4 and NF-{kappa}B co-occupy the same genomic loci on enhancers associated with STING and IL1{beta}, indicating a functional interplay between SMARCA4 and NF-{kappa}B. Taken together, our findings provide the mechanistic basis for the poor response of SMARCA4-mutant tumors to anti-PD1 immunotherapy and establish a functional link between SMARCA4 and NF-{kappa}B on innate immune and inflammatory gene expression regulation.

immunology↗

bioRxiv2024

The silicon transporters (SITs) gene was found in Synechococcus sp. XM24

Silicate serves as a crucial nutrient for diatoms, which are capable of absorbing dissolved silicon from their surroundings through silicon transporters (SITs), thus playing a significant role in the global oceans silicon cycle. Recent studies have indicated that marine single-celled Synechococcus also has the ability to accumulate silicon. Given that the evolution of Synechococcus predates that of diatoms, it is postulated that Synechococcus may utilize transporters such as SITs found in diatoms, to absorb dissolved silicon in the ocean. This research delves into the silicon accumulation in Synechococcus sp. XM24, particularly focusing on two key aspects. Firstly, the study investigates the potential presence of SITs in Synechococcus sp. XM24 under the condition of Depleted-Repleted silicate. Subsequently, two gene sequences suspected to encode SITs, were identified, and their protein sequences and functions were successfully predicted, shedding light on their involvement in membrane transport processes.

microbiology↗

bioRxiv2024

Single-Cell and Spatial Transcriptomic Analyses Reveals the Dynamic Transcript Profiles of Myocardial Lymphangiogenesis post Myocardial Infarction

Cardiac lymphatics play an important role in myocardial edema and inflammation. This study integrated single-cell sequencing data and spatial transcriptome data from mouse heart tissue at different time points post-myocardial infarction (MI), and identified four transcriptionally distinct subtypes of lymphatic endothelial cells (LECs) and localized them in space. Interestingly, LECs subgroups was found to be localized in different zones of infarcted heart related to different functions. Additionally, LEC capillary III(LEC ca III) may be involved in the direct regulation of myocardial injuries in infarcted zone from the perspective of metabolic stress, while LEC ca II may be related to the rapid immune inflammatory responses of the border zone in the early stage of MI. LEC ca I, as well as LEC collection mainly participate in the regulation of myocardial tissue edema resolution in the middle and late stages post-MI. Cell trajectory and Cell-Chat analyses further identified that LECs may regulate myocardial edema through Aqp1, and might affect the infiltration of macrophages through the Galectin9-CD44 pathway. Collectively, our study revealed the dynamic transcriptional heterogeneity distribution of LECs in different regions of the infarcted heart, in detail; these LECs formed different functional subgroups, that might exhibit different bioeffects in myocardial tissue post-MI.

bioinformatics↗

bioRxiv2024

Viral diversiy within marine biofilms and their potential roles in microbially influenced corrosion

In marine environments, a wide variety of microbes exert an important influence on the corrosion of materials. Viruses are widely distributed in biofilms formed on materials and may influence the corrosion process through interactions with key corrosive microbes. However, our understanding of the viral communities within biofilms and their implications for corrosion remains notably limited. To fill this knowledge gap, we utilized 53 publicly metagenomes to investigate the ecological dynamics of viruses within biofilms on 8 different materials and their potential roles in the corrosion of materials. In biofilms, the type of materials may be the primary factor driving differences in the diversity of viral communities. Viruses within biofilms predominantly belong to Caudoviricetes, and phylogenetic analysis of Caudoviricetes and protein-sharing networks with other environments revealed the presence of numerous novel viral clades in biofilms. The presence of virus-host linkages revealed a close association between viruses and corrosive microbes in biofilms. Viruses play a key role in corrosion by modulating host corrosion-related metabolism. It was observed that viruses could enhance host resistance to metals and antibiotics via horizontal gene transfer. Furthermore, viruses can protect themselves from host antiviral systems through anti-defense systems. Overall, this work illustrates the diversity of viruses within biofilms formed on materials and the intricate interactions between viruses and corrosive microbes, revealing the potential roles of viruses in microbially influenced corrosion.

microbiology↗

bioRxiv2024

Cold seeps are hotspots of deep-sea nitrogen-loss driven by microorganisms across 21 phyla

Nitrogen bioavailability, governed by the balance of fixation and loss processes, is a key factor regulating oceanic productivity, ecosystem functions, and global biogeochemical cycles. The key nitrogen-loss organisms--denitrifiers and anaerobic ammonium-oxidizing (anammox) bacteria--are not well understood in marine seafloor environments, especially in deep-sea cold seeps. In this study, we combined geochemical measurements, 15N stable isotope tracer analysis, metagenomics, metatranscriptomics, and three-dimensional protein structural simulations to investigate the diversity of denitrifying and anammox microbial communities and their biogeochemical roles in these habitats. Geochemical evidence from 301 sediment samples shows significantly higher nitrogen-loss rates in cold seeps compared to typical deep-sea sediments, with an estimated annual nitrogen loss of 6.16 Tg from seafloor surface sediments. Examination of a total of 147 million non-redundant genes reveals a high prevalence and active expression of nitrogen-loss genes, including nitrous-oxide reductase (NosZ; 6.88 genes per million or GPM on average), nitric oxide dismutase (Nod; 1.29 GPM), and hydrazine synthase (HzsA; 3.35 GPM) in surface sediments. Analysis of 3,164 metagenome-assembled genomes from this habitat has expanded the known diversity of nitrous-oxide reducers to six phyla and nitric oxide-dismutating organisms to one phylum and two new orders, while ten phyla host anammox bacteria going beyond Planctomycetota. These microbes show diverse structural adaptations and complex gene cluster arrangements that potentially enable survival in the harsh conditions of cold seeps. These findings suggest that cold seeps, despite their low temperatures, are significant, previously underestimated hotspots of nitrogen loss, potentially contribute substantially to the global nitrogen cycle.

microbiology↗

bioRxiv2024

ApoE ϵ4-dependent alteration of CXCR3+CD127+ CD4+ T cells is associated with elevated plasma neurofilament light chain in Alzheimer's disease

Recent findings indicate a correlation between the peripheral adaptive immune system and neuroinflammation in Alzheimers disease (AD). To characterize the composition of adaptive immune cells in the peripheral blood of AD patients, we utilized single-cell mass cytometry (CyTOF) to profile peripheral blood mononuclear cells (PBMCs). Concurrently, we assessed the concentration of proteins associated with AD and neuroinflammation in the plasma of the same subjects. We found that the abundance of proinflammatory CXCR3+CD127+ Type 1 T helper (Th1) cells in AD patients was negatively correlated with the abundance of neurofilament light chain (NfL) protein. This correlation is apolipoprotein E (ApoE) {varepsilon}4-dependent. Analyzing public single-cell RNA-sequencing (scRNA-seq) data, we found that, contrary to the scenario in the peripheral blood, the cell frequency of CXCR3+CD127+ Th1 cells in the cerebrospinal fluid (CSF) of AD patients was increased compared to healthy controls (HCs). Moreover, the proinflammatory capacity of CXCR3+CD127+ Th1 cells in the CSF of AD patients was further increased compared to HCs. These results reveal an association of a peripheral T-cell change with neuroinflammation in AD and suggest that dysregulation of peripheral adaptive immune responses, particularly involving CXCR3+CD127+ Th1 cells, may potentially be mediated by factors such as ApoE {varepsilon}4 genotype. One sentence summaryAn apolipoprotein E (ApoE) {varepsilon}4-dependent alteration of CD4 T cell subpopulation in peripheral blood is associated with neuroinflammation in patients with Alzheimers disease.

immunology↗

bioRxiv2024

Silicification of Cyanobacteria

The ability to use dissolved silicon has been found in various oceanic phytoplankton, including eukaryotic diatoms and prokaryotic cyanobacteria. While the silicification process in diatoms has been extensively studied, it is poorly known in cyanobacteria. In this study, the Cyanobacteria (Synechococcus) silicification and its evolutionary relationships of silicon-related proteins with different phytoplankton and algae were compared. Results showed that, compared to others, cyanobacteria have similar silicification proteins as diatoms. In detail, cyanobacteria and diatoms displayed three silicification-related proteins (SIT, Silaffins, and Pleuralins), while several genera showed one or two of them, suggesting that cyanobacteria might have developed a Si related mechanism earlier than the diatoms and other species. Our findings show that, despite cyanobacterias earlier silicon mechanism compared to others, they might not use efficient Si accumulation, perhaps adapting unique intracellular elemental variation for their cellular processes for growth potential.

evolutionary biology↗

bioRxiv2024

Hypergraph Cortical Cytoarchitectonic Parcellation with Multimodal Canine Brain Atlas

Brain atlases are vital tools in exploring the brain structure-function relationship. The burgeoning cross-species atlases have significantly accelerated our understanding of human brain development, evolution, function, and diseases. However, the existing coarse-grained macroscopic canine brain atlases greatly constrain their utility as an animal model for neurocognition research. Finer-grained brain atlas and partitions are crucial for decoding brain spatial heterogeneity and topology at different scales. Therefore, we conduct macroscopic and microscopic brain imaging to construct an interactive online dataset of multimodal canine brain atlas. Additionally, we develop a pioneering method for cortical cytoarchitectonic partitioning based on hypergraph learning. By integrating high-dimensional cytoarchitectonic features and spatial connections between cortical columns, the method leads to fine-grained partitioning patterns. This innovative approach aims to decode the biological heterogeneity of cortical microstructures, contributing to the structural annotation of canine atlas as well as public human brain atlases. The study not only offers valuable resources but also presents a novel zonation approach to investigate the cellular organization pattern and topology of the cortex.

neuroscience↗

bioRxiv2024

Evolutionary analysis of paired box gene family and biological function exploration of Lr.Pax7 in lamprey (Lethenteron reissneri)

The Pax(paired box)gene family comprises highly conserved transcription factors that play a crucial regulatory role in embryonic development, tissue morphogenesis, and cell differentiation. The gene family comprises of nine members, namely Pax1 to Pax9, each exhibiting distinct functionalities and expression patterns. Among the members of the Pax family, Pax7 is particularly involved in key regulatory functions related to skeletal muscle development and satellite cell biology in vertebrates. However, the precise role of Pax7 and its downstream targets in jawless vertebrates such as lamprey remains relatively understudied. Therefore, investigating the expression and function of lampreys Pax genes holds significant value as a model organism for understanding developmental processes, evolution, and interactions with other vertebrates. In this study, we identified Pax7 in Lethentero reissneri and multiple bioinformatics analyses suggested that it may represent the ancestral gene of the Pax7 shared among higher vertebrates. To further elucidate the function and regulatory mechanism of Pax7, we performed transcriptome sequencing analysis after silencing Lr.Pax7 expression which revealed alterations in metabolic processes along with associated genes(Plcy,Jagged2,Hes,Myod,Frizzled2,etc) involved in various immune pathways(Notch, Wnt, IL-17, TNF, etc), myogenesis process, adipocyte formation process consistent with those observed in higher vertebrates. Comparative studies between lamprey and high vertebrates could provide valuable insight into understanding the functional role of Pax7 and its downstream targets across diverse biological process as well as disease states.

evolutionary biology↗

bioRxiv2024

FKBP11 targeted plasma cells promote abdominal aortic aneurysm progression through an m6A-dependent mechanism

ObjectiveDespite surgical advance, effective targeted drugs for non-surgical treatment of abdominal aortic aneurysm (AAA) are lacking because of the unclear pathogenesis of AAA. N6-methyladenosine (m6A) methylation, acknowledged for its pivotal influence on RNA metabolism, including aspects such as stability, transport, translation, and splicing, is largely implied for its role in AAA mechanism. This study aims to elucidate the involvement of m6A methylation in the progression of AAA through an integrative multi-omics and machine learning approach. Methods and ResultsWe utilized methylated RNA immunoprecipitation sequencing (MeRIP-seq) to map the m6A methylation landscape in AAA tissues and combined this with RNA sequencing (RNA-seq) from the GEO database, to explore the interplay between m6A methylation and gene expression. A machine learning-based AAA m6A-related mRNA signature (AMRMS) was developed to predict the risk of AAA dilation. The AMRMS showed robust predictive power in distinguishing between patients with large and small AAAs. Notably, FKBP11 was identified as a key gene significantly influencing the predictive model, and up-regulated in large AAAs compared to its in small AAAs. Further single-cell RNA sequencing (scRNA-seq) and histological analysis highlighted the critical role of FKBP11 in mediating the endoplasmic reticulum stress of plasma cells within the AAA walls and its correlation with m6A methylation. ConclusionsThe m6A modification regulatory network plays a vital role in the progression of AAA, and the AMRMS offers promising potential in assessing the risk of AAA dilation. Our findings suggest that elevated FKBP11, by activating endoplasmic reticulum stress in plasma cells, may significantly contribute to AAA expansion.

cell biology↗

bioRxiv2024

Circular DNA vcDNA-S7 derived from segmented-dsRNA virus BmCPV attenuated viral infection through RNase H1

Viral circDNA derived from insect positive-sense single-stranded RNA viruses plays a crucial role in regulating viral infections depending on the RNAi pathway. Our previous research has revealed that Bombyx mori cypovirus (BmCPV), a segmented-dsRNA virus, can generate viral circDNA vcDNA-S7, which can be transcribed to form RNA and further processed into small RNAs to defend against the virus through RNAi. However, whether vcDNA-S7 employs other mechanisms to resist the viruses. Presently, vcDNA-S7 has been found to resist BmCPV infection via a novel mechanism that depends on ribonuclease RNase H1 activity. It was found that the expression level of RNase H1 increased upon BmCPV infection (RNA virus) but not upon B. mori nucleopolyhedrovirus (BmNPV) (DNA virus) infection. RNase H1 has been shown to negatively regulate BmCPV infections. In addition, vcDNA-S7 was found to form a heteroduplex with the viral RNA and subsequently recruit RNase H1 to degrade the viral RNA within the heteroduplex, ultimately leading to the suppression of viral replication. Furthermore, the resistance of vcDNA-S7 to viruses was significantly reduced when cellular RNase H1 gene was silenced. These findings not only reveal a new antiviral mechanism involving circular DNA formed by reovirus but also offer intriguing insights into the antiviral function of RNase H1 in cells.

immunology↗

bioRxiv2024

Transcriptome-wide identification of 5-methylcytosine by deaminase and reader protein-assisted sequencing

5-Methylcytosine (m5C) is one of the post-transcriptional modifications in mRNA and is involved in the pathogenesis of various diseases. However, the capacity of existing assays for accurately and comprehensively transcriptome-wide m5C mapping still needs improvement. Here, we develop a detection method named DRAM (deaminase and reader protein assisted RNA methylation analysis), in which deaminases (APOBEC1 and TadA-8e) are fused with m5C reader proteins (ALYREF and YBX1) to identify the m5C sites through deamination events neighboring the methylation sites. This antibody-free and bisulfite-free approach provides transcriptome-wide editing regions which are highly overlapped with the publicly available BS-seq datasets and allows for a more stable and comprehensive identification of the m5C loci. In addition, DRAM system even supports ultra-low input RNA (10ng). We anticipate that the DRAM system could pave the way for uncovering further biological functions of m5C modifications.

biochemistry↗

bioRxiv2024

A Ratiometric Catalog of Protein Isoform Shifts in the Cardiac Fetal Gene Program

Pathological cardiac remodeling is associated with the reactivation of fetal genes, yet the extent of the hearts fetal gene program and its impact on proteome compositions remain incompletely understood. Here, using a new proteome-wide protein ratio quantification strategy with mass spectrometry, we identify pervasive isoform usage shifts in fetal and postnatal mouse hearts, involving 145 pairs of highly homologous paralogs and alternative splicing-derived isoform proteins. Proteome-wide ratio comparisons readily rediscover hallmark fetal gene signatures in muscle contraction and glucose metabolism pathways, while revealing novel isoform usage in mitochondrial and gene expression proteins, including PPA1/PPA2, ANT1/ANT2, and PCBP1/PCBP2 switches. Paralogs with differential fetal usage tend to be evolutionarily recent, consistent with functional diversification. Alternative splicing adds another rich source of fetal isoform usage differences, involving PKM M1/M2, GLS-1 KGA/GAC, PDLIM5 long/short, and other spliceoforms. When comparing absolute protein proportions, we observe a partial reversion toward fetal gene usage in pathological hearts. In summary, we present a ratiometric catalog of paralogs and spliceoform pairs in the cardiac fetal gene program. More generally, the results demonstrate the potential of applying the proteome-wide ratio test concept to discover new regulatory modalities beyond differential gene expression.

biochemistry↗

bioRxiv2024

Structural basis for Retriever-SNX17 assembly and endosomal sorting

During endosomal recycling, Sorting Nexin 17 (SNX17) facilitates the transport of numerous membrane cargo proteins by tethering them to the Retriever complex. Despite its importance, the mechanisms underlying this interaction have remained elusive. Here, we report the structure of the Retriever-SNX17 complex determined using cryogenic electron microscopy (cryo-EM). Our structure reveals that the C-terminal tail of SNX17 engages with a highly conserved interface between the VPS35L and VPS26C subunits of Retriever. Through comprehensive biochemical, cellular, and proteomic analyses, we demonstrate that disrupting this interface impairs the Retriever-SNX17 interaction, subsequently affecting the recycling of SNX17-dependent cargos and altering the composition of the plasma membrane proteome. Intriguingly, we find that the SNX17-binding pocket on Retriever can be utilized by other ligands that share a consensus acidic C-terminal tail motif. By showing how SNX17 is linked to Retriever, our findings uncover a fundamental mechanism underlying endosomal trafficking of critical cargo proteins and reveal a mechanism by which Retriever can engage with other regulatory factors.

biochemistry↗

bioRxiv2024

Discovery of the First-in-class G9a/GLP PROTAC Degrader

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader, 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/582210v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1b3c923org.highwire.dtl.DTLVardef@5a22f0org.highwire.dtl.DTLVardef@1abbabeorg.highwire.dtl.DTLVardef@1711f29_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗