Biology subjects

Yi, S.

Publications and source records attributed to Yi, S..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

New Atg9 phosphorylation sites regulate autophagic trafficking in glia

We previously identified a role for dAuxilin (dAux), the fly homolog of Cyclin G-associated kinase (GAK), in glial autophagy contributing to Parkinsons disease (PD). To further dissect the mechanism, we present evidence here that lack of glial dAux enhanced the phosphorylation of the autophagy-related protein Atg9 at two newly identified threonine residues, T62 and T69. Enhanced Atg9 phosphorylation in the absence of glial dAux is potentially regulated through the master autophagy regulator Atg1, as the presence of which is required for Atg9 to interact with dAux in an otherwise separate condition. The enhanced Atg9 phosphorylation promotes autophagosome formation and Atg9 trafficking to the autophagosomes in glia. Whereas the expression of the non-phosphorylatable Atg9 variants suppresses the lack of dAux-induced increase in both autophagosome formation and Atg9 trafficking to autophagosome, the expression of the phophomimetic Atg9 variants restores the lack of Atg1-induced decrease in both events. Notably, Atg9 phosphorylation at T62 and T69 contributes to DA neurodegeneration and locomotor dysfunction implicated in PD. Thus, we have identified a dAux-Atg1-Atg9 axis relaying signals through the Atg9 phosphorylation at T62 and T69; these findings further elaborate the mechanism of dAux regulating glial autophagy and highlight the significance of protein degradation pathway in glia contributing to PD.

neuroscience↗

bioRxiv2024

Human Brain Aging is Associated with Dysregulation of Cell-Type Epigenetic Identity

Significant links between aging and DNA methylation are emerging from recent studies. On the one hand, DNA methylation undergoes changes with age, a process termed as epigenetic drift. On the other hand, DNA methylation serves as a readily accessible and accurate biomarker for aging. A key missing piece of information, however, is the molecular mechanisms underlying these processes, and how they are related, if any. Addressing the limitations of previous research due to the limited number of investigated CpGs and the heterogeneous nature of tissue samples, here we have examined DNA methylation of over 20 million CpGs across a broad age span in neurons and non-neuronal cells, primarily oligodendrocytes. We show that aging is a primary predictor of DNA methylation variation, surpassing the influence of factors such as sex and schizophrenia diagnosis, among others. On the genome-wide scale, epigenetic drift manifests as significant yet subtle trends that are influenced by the methylation level of individual CpGs. We reveal that CpGs that are highly differentiated between cell types are especially prone to age-associated DNA methylation alterations, leading to the divergence of epigenetic cell type identities as individuals age. On the other hand, CpGs that are included in commonly used epigenetic clocks tend to be those sites that are not highly cell type differentiated. Therefore, dysregulation of epigenetic cell-type identities and current DNA epigenetic clocks represent distinct features of age-associated DNA methylation alterations.

genetics↗

bioRxiv2024

DNA methylation differences between the female and male X chromosomes in human brain

The mechanisms of X chromosome inactivation suggest fundamental epigenetic differences between the female and male X chromosomes. However, DNA methylation studies often exclude the X chromosomes. In addition, many previous studies relied on techniques that examine non-randomly selected subsets of positions such as array-based methods, rather than assessing the whole X chromosome. Consequently, our understanding of X chromosome DNA methylation lags behind that of autosomes. Here we addressed this gap of knowledge by studying X chromosome DNA methylation using 89 whole genome bisulfite sequencing (WGBS) maps from neurons and oligodendrocytes. Using this unbiased and comprehensive data, we show that DNA methylation of the female X chromosomes is globally reduced (hypomethylated) across the entire chromosome compared to the male X chromosomes and autosomes. On the other hand, the majority of X-linked promoters were more highly methylated (hypermethylated) in females compared to males, consistent with the role of DNA methylation in X chromosome inactivation and dosage compensation. Remarkably, hypermethylation of female X promoters was limited to a group of previously lowly methylated promoters. The other group of highly methylated promoters were both hyper- and hypo-methylated in females with no obvious association with gene expression. Therefore, X chromosome inactivation by DNA methylation was exclusive to a subset of promoters with distinctive epigenetic feature. Apart from this group of promoters, differentially methylated regions in the female and male X chromosomes were dominated by female hypomethylation. Our study furthers the understanding of X-chromosome dosage regulation by DNA methylation on the chromosomal level as well as on individual gene level.

genomics↗

bioRxiv2024

Mitochondrial stress in GABAergic neurons non-cell autonomously regulates organismal health and aging

Mitochondrial stress within the nervous system can trigger non-cell autonomous responses in peripheral tissues. However, the specific neurons involved and their impact on organismal aging and health have remained incompletely understood. Here, we demonstrate that mitochondrial stress in {gamma}-aminobutyric acid-producing (GABAergic) neurons in Caenorhabditis elegans (C. elegans) is sufficient to significantly alter organismal lifespan, stress tolerance, and reproductive capabilities. This mitochondrial stress also leads to significant changes in mitochondrial mass, energy production, and levels of reactive oxygen species (ROS). DAF-16/FoxO activity is enhanced by GABAergic neuronal mitochondrial stress and mediates the induction of these non-cell-autonomous effects. Moreover, our findings indicate that GABA signaling operates within the same pathway as mitochondrial stress in GABAergic neurons, resulting in non-cell-autonomous alterations in organismal stress tolerance and longevity. In summary, these data suggest the crucial role of GABAergic neurons in detecting mitochondrial stress and orchestrating non-cell-autonomous changes throughout the organism.

genetics↗

bioRxiv2024

Evolved and plastic gene expression in adaptation to a novel niche

Gene expression, resulting from complex regulatory interactions, plays an important role in adaptation and speciation. While gene expression historically has been studied in the context of reproductive isolation in speciation research, a role for evolved differences in gene expression in adaptation to novel niches is increasingly appreciated. How gene expression evolves and enables divergent ecological adaptation, and how changes in gene expression relate to genomic architecture and genetic divergence are pressing questions in understanding the processes of adaptation and ecological speciation. Further, how plasticity in gene expression can both contribute to and be affected by the process of ecological adaptation is a crucial component in understanding gene expression evolution. To address these questions, we investigate the role of evolved and plastic gene expression differences in adaptation leveraging an established host plant shift in the peacock fly Tephritis conura. Using a cross-fostering design where larvae feed on either natal or alternate host plants, we uncover extensive evolved differences in gene expression between the ecotypes, strikingly in genes associated with processing of host plant chemicals. We find limited evidence for plasticity, with some indications of higher plasticity in the ancestral ecotype where the expression of three gene coexpression modules is altered when larvae are cross-fostered to the derived host plant. Interestingly, we find an enrichment of differentially expressed genes within a large, ecotype-specific inversion in the T. conura genome. This finding adds to evidence that inversions are important for enabling diversification in the face of gene flow and underscores that effects on gene expression may be key to understanding the role of inversions.

evolutionary biology↗

bioRxiv2024

Super Pangenome of Grapevines Empowers Improvement of the Oldest Domesticated Fruit

Grapevine (Vitis) is the oldest domesticated fruit crop with great cultural and economic importance. Here, we assemble and annotate haplotype-resolved genomes of 72 Vitis accessions including 25 wild and 47 cultivated grapevines, and a haplotype-resolved complete genome of V. vinifera. Coalescent phylogenomics of 142 haplotype genomes disentangles the mysterious hybridization history of grapevines, revealing enormous genetic diversity among species. Pangenome analysis together with phenotyping data reveals that European cultivars, more susceptible to the most destructive disease downy mildew (DM), had a smaller repertoire of disease resistance genes of NLR family. Through extensive structural variation (SV) characterization, phenotyping, transcriptome profiling of 113 Vitis accessions, and SV-eQTL analysis, we have identified over 79 SVs and their relevant genes significantly associated with DM resistance, exemplified by a lysine histidine transporter, VvLHT8. This haplotype-resolved complete genome and pangenome of Vitis genus will accelerate grapevine breeding and enrich our understanding of the evolution and biology of grapevines.

plant biology↗

bioRxiv2024

BMP9 and BMP10 coordinate liver cellular crosstalk to maintain liver health

The liver is the largest solid organ in the body and is primarily composed of HCs, ECs, KCs, and HSCs, which spatially interact and cooperate with each other to maintain liver homeostasis. However, the complexity and molecular mechanisms underlying the crosstalk between these different cell types remain to be revealed. Here, we generated mice with conditional deletion of Bmp9/10 in different liver cell types and demonstrated that HSCs were the major source of BMP9 and BMP10 in the liver. Using transgenic ALK1 (receptor for BMP9/10) reporter mice, we found that ALK1 is expressed on KCs and ECs other than HCs and HSCs, and BMP9/10 secreted by HSCs promotes the differentiation of KCs and ECs and maintain their identity. Pdgfb expression was significantly upregulated in KCs and ECs after BMP9 and BMP10 deletion, ultimately leading to HSCs activation and liver fibrosis. ECs express several angiocrine factors, such as BMP2, BMP6, Wnt2 and Rspo3, to regulate hepatocyte iron metabolism and metabolic zonation. We found that these angiocrine factors were significantly decreased in ECs from Bmp9/10HSC-KO mice, which further resulted in liver iron overload and disruption of HC zonation. In summary, we demonstrated that HSCs play a central role in mediating liver cell-cell crosstalk via the production of BMP9/10, highlighting the important role of intercellular interaction in organ development and homeostasis.

cell biology↗

bioRxiv2024

CAT Bridge: an efficient toolkit for compound-transcript association mining from multi-omics data

BackgroundWith advancements in sequencing and mass spectrometry technologies, multi-omics data can now be easily acquired for understanding complex biological systems. Nevertheless, substantial challenges remain in determining the association between gene-metabolite pairs due to the non-linear and multifactorial interactions within cellular networks. The complexity arises from the interplay of multiple genes and metabolites, often involving feedback loops and time-dependent regulatory mechanisms that are not easily captured by traditional analysis methods. FindingsHere, we introduce Compounds And Transcripts Bridge (abbreviated as CAT Bridge, available at https://catbridge.work), a free user-friendly platform for longitudinal multi-omics analysis to efficiently identify transcripts associated with metabolites using time-series omics data. To evaluate the association of gene-metabolite pairs, CAT Bridge is a pioneering work benchmarking a set of statistical methods spanning causality estimation and correlation coefficient calculation for multi-omics analysis. Additionally, CAT Bridge features an artificial intelligence (AI) agent to assist users interpreting the association results. ConclusionsWe applied CAT Bridge to experimentally obtained Capsicum chinense (chili pepper) and public human and Escherichia coli (E. coli) time-series transcriptome and metabolome datasets. CAT Bridge successfully identified genes involved in the biosynthesis of capsaicin in C. chinense. Furthermore, case study results showed that the convergent cross mapping (CCM) method outperforms traditional approaches in longitudinal multi-omics analyses. CAT Bridge simplifies access to various established methods for longitudinal multi-omics analysis, and enables researchers to swiftly identify associated gene-metabolite pairs for further validation.

bioinformatics↗

bioRxiv2023

A phosphorylation-dependent switch of the lysosomal V-ATPase assembly regulates α-synuclein clearance in glia

Glia serve as double-edged swords to modulate neuropathology in Parkinsons disease (PD), but how they react opposingly to be beneficial or detrimental under pathological conditions, like promoting or eliminating -synuclein (-syn) inclusions, remains elusive. Here we present evidence that dAuxilin (dAux), the Drosophila homolog of the PD risk factor Cyclin G-associated kinase (GAK), regulates the lysosomal degradation of -syn in glia. Lack of glial Gak/dAux increases the lysosome number and size, regulates lysosomal acidification and hydrolase activity, and ultimately blocks the degradation of substrates including -syn. Whereas -syn accumulated prominently in lysosomes devoid of glial dAux, levels of injected -syn preformed fibrils also further enhanced in the absence of microglial Gak. Mechanistically, dAux mediates phosphorylation at the serine 543 of Vha44, the V1C subunit of the vacuolar H+-ATPase (V-ATPase), regulates its assembly to control proper acidification of the lysosomal milieu. Expression of Vha44, but not the Vha44 variant lacking S543 phosphorylation, restores lysosome acidity, locomotor deficits, and DA neurodegeneration upon glial dAux depletion, linking this pathway to PD. Our findings identify a phosphorylation-dependent switch controlling the V-ATPase assembly for lysosomal -syn degradation in glia. Targeting the clearance of glial -syn inclusions via this lysosomal pathway could potentially be a therapeutical approach to ameliorate the disease progression in PD.

neuroscience↗

bioRxiv2023

Co-transcriptional translation amplifies mRNA noise in Escherichia coli

The variability in mRNA expression among isogenic cells exposed to identical environments is inherent. This variability originates from the inherent stochasticity of all processes underlying transcription. Although transcription and translation can occur simultaneously on the same mRNA molecule in bacteria, it is not well understood whether and how co-transcriptional translation contributes to variability in mRNA expression. Here, we studied the contribution of co-transcriptional translation to mRNA noise in E. coli cells. Using a transcription system physically decoupled from translation, we investigated the effect of ribosome binding to mRNA transcripts on variability in mRNA expression. We found that the propagation of RNAP noise to the mRNA level was increased by ribosome binding, leading to larger variations in the mRNA levels. We further demonstrated that ribosome binding increased the transcription initiation rate, resulting in the promoter becoming susceptible to RNAP noise. Co-transcriptional translation amplified transcriptional noise and modulated transcriptional bursting kinetics in bacterial cells.

biophysics↗

bioRxiv2023

Mapping RNA-Protein Interactions with Subcellular Resolution Using Colocalization CLIP

RNA binding proteins (RBPs) are essential for RNA metabolism and profoundly impact health and disease. The subcellular organization of RBP interaction networks with target RNAs remains largely unexplored. Here, we develop colocalization CLIP, a method that combines CrossLinking and ImmunoPrecipitation (CLIP) with proximity labeling, to explore in-depth the subcellular RNA interactions of the well-studied RNA-binding protein HuR. Using this method, we uncover HuRs dynamic and location-specific interactions with RNA, revealing alterations in sequence preferences and interactions in the nucleus, cytosol, or stress granule compartments. We uncover HuRs unique binding preferences within stress granules during arsenite stress, illuminating intricate interactions that conventional methodologies cannot capture. Overall, coCLIP provides a powerful method for revealing RBP:RNA interactions based on localization and lays the foundation for an advanced understanding of RBP models that incorporate subcellular location as a critical determinant of their functions.

molecular biology↗

bioRxiv2023

Gut microbial genomes with paired isolates from China signify probiotic and cardiometabolic effects

The gut microbiome displays significant genetic differences between populations while systematic characterization of the genomic landscape of the gut microbiome in Asia populations remains limited. Here, we present the Chinese gut microbial reference (CGMR) set, comprising 101,060 high quality metagenomic assembled genomes (MAGs) of 3,707 non-redundant species paired with 1,376 live isolates from a national wide collection of 3,234 fecal samples across China. This improved reference set contains 987 novel species compared with existing resources worldwide. By associating MAGs with geographic and phenotypic characteristics, we observed regional-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. We further conducted mice experiments to confirm the probiotic effects of two Faecalibacterium intestinalis isolates in alleviating constipation, the cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and the functional potential of isolates from the two new species belonging to the genera Parabacteroides and Lactobacillus in host lipids metabolism. Our study not only expands the current microbial genomes with paired isolates but also demonstrates their probiotic and cardiometabolic effects on hosts, contributing to the mechanistic understanding of host-microbe interactions and the translation of microbiome-based personalized therapies.

microbiology↗

bioRxiv2023

Pervasive mislocalization of pathogenic coding variants underlying human disorders

Widespread sequencing has yielded thousands of missense variants predicted or confirmed as disease-causing. This creates a new bottleneck: determining the functional impact of each variant - largely a painstaking, customized process undertaken one or a few genes or variants at a time. Here, we established a high-throughput imaging platform to assay the impact of coding variation on protein localization, evaluating 3,547 missense variants of over 1,000 genes and phenotypes. We discovered that mislocalization is a common consequence of coding variation, affecting about one-sixth of all pathogenic missense variants, all cellular compartments, and recessive and dominant disorders alike. Mislocalization is primarily driven by effects on protein stability and membrane insertion rather than disruptions of trafficking signals or specific interactions. Furthermore, mislocalization patterns help explain pleiotropy and disease severity and provide insights on variants of unknown significance. Our publicly available resource will likely accelerate the understanding of coding variation in human diseases.

cell biology↗

bioRxiv2023

Computational and neural mechanisms underlying the influence of action affordances on value-based choice

When encountering a novel situation, an intelligent agent needs to find out which actions are most beneficial for interacting with that environment. One purported mechanism for narrowing down the scope of possible actions is the concept of action affordance. Here, we delve into the neuro-computational mechanisms accounting for how action affordance shapes value-based learning in a novel environment by utilizing a novel task alongside computational modeling of behavioral and fMRI data collected in humans. Our findings indicate that rather than simply exerting an initial or persistent bias on value-driven choices, action affordance is better conceived of as an independent system that concurrently guides action-selection alongside value-based decision-making. These two systems engage in a competitive process to determine final action selection, governed by a dynamic meta controller. We find that the pre-supplementary motor area and anterior cingulate cortex plays a central role in exerting meta-control over the two systems while the posterior parietal cortex integrates the predictions from these two controllers of what action to select, so that the action-selection process dynamically takes into account both the expected value and appropriateness of particular actions for a given scenario.

neuroscience↗

bioRxiv2023

A near-complete genome sequence of einkorn wheat provides insight into the evolution of wheat A subgenomes

Einkorn wheat (Triticum monococcum) is one of the oldest cereal crops to be domesticated by human beings, playing essential role in early agriculture development. Today, it is considered an important genomic resource for modern wheat improvement, especially for resistance against pests and diseases. However, the exploration and utilization of useful genes from T. monococcum is limited due to the lack of a reference genome and annotation for this species. Here, we report a near-complete genome assembly for T. monococcum with a total length of 5.11 Gb with a contig N50 of 131.2Mb and scaffold N50 of 728.66Mb, representing a genome assembly of highest quality for any wheat genome reported. Phylogenomic analysis confirmed T. monococcum is closely-related to T. urartu, the progenitor of wheat A subgenomes. A 4AL/5AL terminal translocation is present in the diploid species T. urartu and T. monococcum, taking place before wheat polyploidization. T. monococcum has significantly expanded and unique gene families involved in DNA damage repair and heat stress tolerance, reflecting its adaptive evolution to cope with historical harsh climate in its natural habitat, South East Turkey. The genome sequence confirmed the introgression of T. monococcum rust resistance genes at 5AmL into modern bread wheat varieties. This near-complete reference genome of T. monococcum will be an essential resource for wheat functional and evolutionary genomic studies and expedite the cloning of useful genes in T. monococcum for future wheat improvement.

genomics↗

bioRxiv2023

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease

Parkinsons disease (PD) is a progressive neurodegenerative disorder characterized by the motor deficits, selective loss of dopaminergic (DA) neurons, and the brain accumulation of -synuclein (-syn)-composed protein aggregates called Lewy bodies (LBs). Whereas dysfunction in the protein degradation pathway, like autophagy in neurons, has been demonstrated as a critical mechanism for eliminating protein aggregates in PD, how protein aggregates are eliminated in the other brain cell type, glia, is less well characterized. In the present study, we show that Atg9, the only transmembrane protein in the core autophagy pathway, is highly expressed in Drosophila adult brain glia. Results from immunostaining and live-cell imaging analysis reveal that a significant portion of Atg9 localizes to the trans-Golgi network (TGN), autophagosomes, and lysosomes in glia; Atg9 is persistently in contact with these organelles. Lacking glial atg9 reduces the number of omegasome and autophagosome and impairs autophagic substrate degradation, suggesting that glial Atg9 participates in the early steps of autophagy, hence the control of autophagic degradation. Importantly, loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive DA neuron loss and locomotion deficits. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and PD. These results provide new insights on the underlying mechanism of PD.

neuroscience↗

bioRxiv2022

Shaping neonatal immunization by tuning delivery of synergistic adjuvants via nanocarriers

Adjuvanted nanocarrier-based vaccines hold substantial potential for applications in novel early-life immunization strategies. Here, via mouse and human age-specific in vitro modelling, we identified the combination of a small molecule STING agonist (2'3'-cyclic GMP-AMP, cGAMP) and a TLR7/8 agonist (CL075) to drive synergistic activation of neonatal dendritic cells and precision CD4 Th cell expansion via the IL-12/IFN{gamma} axis. We further demonstrate that vaccination of neonatal mice with quadrivalent influenza recombinant hemagglutinin (rHA) and an admixture of two polymersome (PS) nanocarriers separately encapsulating-cGAMP (cGAMP-PS) and CL075 (CL075-PS) drove robust T helper (Th)1 bias, high frequency of T follicular helper (TFH) cells and germinal center B (GC B) cells along with IgG2c-skewed humoral response in vivo. Dual loaded cGAMP/CL075-PSs did not outperform admixed cGAMP-PSs and CL075-PSs in vivo. These data validate an optimally designed adjuvantation system, via age-selected small molecule synergy and a multi-component nanocarrier formulation, as an effective approach to induce type 1 immune responses in early life.

immunology↗

bioRxiv2022

Resetting of H3K4me2 during mammalian parental-to-zygote transition

Upon sperm and oocyte fertilization, the embryo undergoes drastic histone modification reprogramming during pre-implantation development. In this study, we investigated the erasure and re-establishment of H3K4me2 in mouse GV, MII, and embryos using an improved approach called Cleavage Under Targets and Release Using Nuclease (CUT&RUN) with high-throughput sequencing. We found that H3K4me2 extensively occurs as a non-canonical pattern in mouse GV oocytes and early embryos, and parental H3K4me2 was erased by maternal LSD2 during forming the pronucleus in the zygote. The H3K4me2 was erased from GV to MII oocyte and was re-established in the late two-cell stage, removing this epigenetic burden is crucial for ZGA. We then revealed the H3K4me2 locates widespread in the CpG-rich and hypomethylated regulatory regions in the four-cell stage, and the eight-cell stage, but dramatic changes occurred in the inner cell mass (ICM) in mouse embryos. Then, these CpG-rich H3K4me2 regulatory regions became either activated or repressed. To summarize, in this study, we elucidated the pattern of H3K4me2 transition from parent to zygote and H3K4me2 profile during early embryo development. Our findings might provide deeper insights into epigenetic reprogramming during early development and in vitro fertilization in mammalian. HighlightsO_LIH3K4me2 showed differential patterns in sperms and oocytes; non-canonical pattern occurred in GV oocytes, but canonical patterns were found in the sperm cells of mice. C_LIO_LIThe H3K4me2 peaks of GV were almost erased in MII oocytes and reconstructed after the major ZGA occurred. Maternal LSD2 was found to regulate H3K4me2 resetting during the parental-to-zygote transition. H3K4me2 may impose an "Epigenetic Burden" on ZGA. C_LIO_LINon-canonical H3K4me2 pattern was found in mammalian embryos, however, pervasive H3K4me2 in CpG-rich regulatory regions were found in four-cell and eight-cell stage embryos; The CpG-rich H3K4me2 regulatory regions were either activated or repressed in the ICM. C_LI

genetics↗