Biology subjects

LI, Y.

Publications and source records attributed to LI, Y..

25 records · Page 2Linked to original sources

bioRxiv2023

Human Gut Microbial Sulfonolipids are linked to Inflammatory Bowel Diseases through Toll-Like Receptor 4 Signaling

The trillions of microorganisms inhabiting the human gut are intricately linked to human health. At the species abundance level, correlational studies have connected specific bacterial taxa to various diseases. While the abundances of these bacteria in the gut serve as good indicators for disease progression, understanding the functional metabolites they produce is critical to decipher how these microbes influence human health. Here, we report a unique biosynthetic enzyme-guided disease correlation approach to uncover microbial functional metabolites as potential molecular mechanisms in human health. We directly connect the expression of gut microbial sulfonolipid (SoL) biosynthetic enzymes to inflammatory bowel disease (IBD) in patients, revealing a negative correlation. This correlation is then corroborated by targeted metabolomics, identifying that SoLs abundance is significantly decreased in IBD patient samples. We experimentally validate our analysis in a mouse model of IBD, showing that SoLs production is indeed decreased while inflammatory markers are increased in diseased mice. In support of this connection, we apply bioactive molecular networking to show that SoLs consistently contribute to the immunoregulatory activity of SoL-producing human microbes. We further reveal that sulfobacins A and B, two representative SoLs, primarily target Toll-like receptor 4 (TLR4) to mediate immunomodulatory activity through blocking TLR4s natural ligand lipopolysaccharide (LPS) binding to myeloid differentiation factor 2, leading to significant suppression of LPS-induced inflammation and macrophage M1 polarization. Together, these results suggest that SoLs mediate a protective effect against IBD through TLR4 signaling and showcase a widely applicable biosynthetic enzyme-guided disease correlation approach to directly link the biosynthesis of gut microbial functional metabolites to human health.

biochemistry↗

bioRxiv2021

The First High-Quality Reference Genome of Sika Deer Provides Insights for High-Tannin Adaptation

Sika deer are known to prefer oak leaves, which are rich in tannins and toxic to most mammals; however, the genetic mechanisms underlying their unique ability to adapt to living in the jungle are still unclear. In identifying the mechanism responsible for the tolerance of a highly toxic diet, we have made a major advancement in the elucidation of the genomics of sika deer. We generated the first high-quality, chromosome-level genome assembly of sika deer and measured the correlation between tannin intake and RNA expression in 15 tissues through 180 experiments. Comparative genome analyses showed that the UGT and CYP gene families are functionally involved in the adaptation of sika deer to high-tannin food, especially the expansion of UGT genes in a subfamily. The first chromosome-level assembly and genetic characterization of the tolerance toa highly toxic diet suggest that the sika deer genome will serve as an essential resource for understanding evolutionary events and tannin adaptation. Our study provides a paradigm of comparative expressive genomics that can be applied to the study of unique biological features in non-model animals.

genomics↗

bioRxiv2020

A Novel Regulatory Role for the Circadian Clock Protein TOC1 via RNA binding

The circadian clock enables plants to predict daily changes of external signals and synchronize them with internal processes, conferring enhanced fitness and growth vigor. The first described Arabidopsis circadian clock protein is TIMING OF CAB EXPRESSION 1 (TOC1), which functions in a transcriptional feedback loop with two myb transcription factors, CIRCADIAN CLOCK-ASSOCIATED 1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY). Previous studies have shown that TOC1 is a DNA-binding transcriptional repressor of CCA1 and LHY. However, the DNA motifs enriched amongst TOC1 targets share weak sequence similarity and lack consensus, suggesting that TOC1 regulates the expression of its targets through a novel mechanism. Here we show that the TOC1 protein binds directly to RNA via its conserved CCT domain. Using in vitro RNA selection, we identified an RNA motif that is recognized by the TOC1-CCT domain. The TOC1-CCT domain binds to this RNA sequence with nanomolar affinity determined by quantitative electrophoretic mobility shift assays (EMSAs) and isothermal titration calorimetry (ITC). NMR experiments showed that two CCT fragments, CCT533-547 and CCT550-565, use basic residues to bind the RNA motif. Mutational analysis confirmed that lysyl and arginyl residues bind to RNA in a cooperative manner. Furthermore, transiently expressed wildtype and mutant TOC1 in protoplasts demonstrated that RNA binding activity of TOC1 is required for its function as a transcriptional repressor in vivo. Our results reveal a novel regulatory mechanism for TOC1 through RNA binding, suggesting that TOC1 might play key roles as a multi-function protein.

plant biology↗

bioRxiv2020

Nanoscale Chromatin Imaging and Analysis (nano-ChIA) platform bridges 4-D chromatin organization with molecular function

In eukaryotic cells, chromatin structure is linked to transcription processes through the regulation of genome organization. Extending across multiple length-scales - from the nucleosome to higher-order three-dimensional structures - chromatin is a dynamic system which evolves throughout the lifetime of a cell. However, no individual technique can fully elucidate the behavior of chromatin organization and its relation to molecular function at all length- and timescales at both a single-cell and a cell population level. Herein, we present a multi-technique nanoscale Chromatin Imaging and Analysis (nano-ChIA) platform that bridges electron tomography and optical superresolution imaging of chromatin conformation and transcriptional processes, with resolution down to the level of individual nucleosomes, with high-throughput, label-free analysis of chromatin packing and its dynamics in live cells. Utilizing nano-ChIA, we observed that chromatin is localized into spatially separable packing domains, with an average diameter of around 200 nm, sub-Mb genomic size, and an internal fractal structure. The chromatin packing behavior of these domains is directly influenced by active gene transcription. Furthermore, we demonstrated that the chromatin packing domain structure is correlated among progenitor cells and all their progeny, indicating that the organization of chromatin into fractal packing domains is heritable across cell division. Further studies employing the nano-ChIA platform have the potential to provide a more coherent picture of chromatin structure and its relation to molecular function.

genomics↗

bioRxiv2019

Association analysis of loci implied in “buffering” epistasis

The existence of buffering mechanisms is an emerging property of biological networks, and this results in the possible existence of \"buffering\" loci, that would allow buildup of robustness through evolution. So far, there are no explicit methods to find loci implied in buffering mechanisms. However, buffering can be seen as interaction with genetic background. Here we develop this idea into a tractable model for quantitative genetics, in which the buffering effect of one locus with many other loci is condensed into a single (statistical) effect, multiplicative on the total (statistical) additive genetic effect. This allows easier interpretation of the results, and it also simplifies the problem of detecting epistasis from quadratic to linear in the number of loci. Armed with this formulation, we construct a linear model for genome-wide association studies that estimates, and declares significance, of multiplicative epistatic effects at single loci. The model has the form of a variance components, norm reaction model and likelihood ratio tests are used for significance. This model is a generalization and explanation of previous ones. We then test our model using bovine data: Brahman and Tropical Composite animals, phenotyped for body weight at yearling and genotyped up to [~]770,000 Single Nucleotide Polymorphisms (SNP). After association analysis and based on False Discovery Rate rules, we find a number of loci with buffering action in one, the other, or both breeds; these loci do not have significant statistical additive effect. Most of these loci have been reported in previous studies, either with an additive effect, or as footprints of selection. We identify epistatic SNPs present in or near genes encoding for proteins that are functionally enriched for peptide activity and transcription factors reported in the context of signatures of selection in multi-breed cattle population studies. These include loci known to be associated with coat color, fertility and adaptation to tropical environments. In these populations we found loci that have a non-significant statistical additive effect but a significant epistatic effect. We argue that the discovery and study of loci associated with buffering effects allows attacking the difficult problems, among others, of release of maintenance variance in artificial and natural selection, of quick adaptation to the environment, and of opposite signs of marker effects in different backgrounds. We conclude that our method and our results generate promising new perspectives for research in evolutionary and quantitative genetics based on the study of loci that buffer effect of other loci.

genetics↗

bioRxiv2019

Tissue-specific MicroRNA Expression Alters Cancer Susceptibility Conferred by a TP53 Noncoding Variant

Patients carrying TP53 germline mutations develop Li-Fraumeni syndrome (LFS), a rare genetic disorder with high risk of several cancers, most notably breast cancer, sarcoma, and brain tumors. A noncoding polymorphism (rs78378222) in TP53, carried by scores of millions of people, was associated with moderate risk of brain, colon, and prostate tumors, and other neoplasms. We found a positive association between this variant and soft tissue sarcoma (odds ratio [OR] = 4.55, P = 3.3 x 10-5). In sharp contrast, this variant was protective against breast cancer (OR = 0.573, P = 0.0078). We generated a mouse line carrying this variant and found that this variant accelerated spontaneous tumorigenesis and tumor development at the brain, prostate, colon, and skeletal muscle, but strikingly, it significantly delayed mammary tumorigenesis. The variant created a miR-382 targeting site and compromised a miR-325 targeting site. Their differential expression resulted in p53 downregulation in the brain and several other tissues, but p53 upregulation in the mammary gland of the mutant mice compared to that of wild-type littermates. Thus, this TP53 variant is at odds with LFS mutants in breast cancer predisposition yet consistent with LFS mutants in susceptibility to soft tissue sarcoma and glioma. Our findings elucidate an underlying mechanism of cancer susceptibility that is conferred by genetic variation and yet altered by microRNA expression.

cancer biology↗

bioRxiv2019

EK-DRD: a comprehensive database for drug repositioning inspired by experimental knowledge

SummaryDrug repositioning, or the identification of new indications for approved therapeutic drugs, has gained substantial traction with both academics and pharmaceutical companies because it reduces the cost and duration of the drug development pipeline and it reduces the likelihood of unforeseen adverse events. So far, there has not been a systematic effort to identify such opportunities, in part because of the lack of a comprehensive resource for an enormous amount of unsystematic drug repositioning information to support scientists who could benefit from this endeavor. To address this challenge, we developed a new database, Experimental Knowledge-Based Drug Repositioning Database (EK-DRD) by using text and data mining, as well as manual curation. EK-DRD contains experimentally validated drug repositioning annotation for 1861 FDA-approved and 102 withdrawn small molecule drugs. Annotation was done at four levels, using 70,212 target assay records, 3999 cell assay records, 585 organism assay records, and 8910 clinical trial records. Additionally, approximately 1799 repositioning protein or target sequences coupled with 856 related diseases and 1332 pathways are linked to the drug entries. Our web-based software displays a network for integrative relationships between drugs, their repositioning targets, and related diseases. The database is fully searchable and supports extensive text, sequence, chemical structure, and relational query searches.\n\nAvailabilityEK-DRD is freely available at http://www.idruglab.com/drd/index.php.\n\nContactlingwang@scut.edu.cn.

bioinformatics↗