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Biology subjects

Lian, J.

Publications and source records attributed to Lian, J..

At least 19 recordsLinked to original sources

Beyond straight lines: migration costs considering geography enhance tracing human genetic ancestry

Reconstructing the spatio-temporal history of human genetic lineages is fundamental to understanding human evolution and population distribution. While succinct tree sequences and maximum parsimony reconstruction methods applied to large-scale genomic data have improved our ability to trace the geographic history of genetic ancestry, they have essentially relied on Euclidean distances, which ineluctably ignore opportunity costs that have shaped human mobility patterns since the earliest human migrations and settlement formations. Here we propose an approach to incorporate realistic geographical migration costs through a human movement friction surface. Using simulated data mimicking the dispersal process of human migration out of Africa, we found that, compared to the Euclidean-based benchmark (M0), the proposed friction-based model (Mf) leads to a more accurate estimation of the geographical origin (n = 346, accuracy M0 = 0.18, f = 0.27) and genetic flux (n = 30, MSE M0 = 0.20, Mf = 0.12) through the Mandeb corridor in the Horn of Africa. We further illustrate these findings in a case study, in which our model seems to better identify plausible human migration paths from Eurasia to the Americas by accounting for geographic factors affecting migration opportunity costs, such as the Alaska Range and Rocky Mountains that represent physical barriers that constraint migration. While important migration drivers such as climate change, technological advances, social organization, and culture remain omitted here, our work highlights the importance of explicitly accounting for geographic constraints to improve our ability to reconstruct past human mobility and, ultimately, understand the evolution of human populations.

evolutionary biology↗

Endoplasmic Reticulum Associated Lipolysis Regulates Hepatic Fat Synthesis and Turnover

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is characterized and initiated by the excessive accumulation of triacylglycerols (TG) and cholesteryl esters (CE) in the liver. Hepatic TG and CE synthesis, lipolysis and transport are tightly regulated by nutritional status, and disruption of this homeostasis contributes to MASLD pathogenesis. We have found that an endoplasmic reticulum-localized arylacetamide deacetylase (AADAC) catalyzes hepatic TG/CE turnover, and suppresses SREBP- and LXR-regulated lipogenesis and fatty acid esterification. Consequently, AADAC deficiency in mice leads to increased hepatic lipid synthesis, exacerbated steatosis, and impaired whole-body metabolism during Western-type diet feeding. These findings implicate AADAC as an important regulator of hepatic neutral lipid metabolism, linking endoplasmic reticulum cholesteryl ester hydrolysis as a modulator of lipid synthesis, and suggest its potential role in limiting MASLD pathogenesis under conditions of chronic overnutrition.

physiology↗

A cinnamyl alcohol dehydrogenase scaffold organizes monoterpenoid indole alkaloid biosynthesis

Biosynthesis of ~3,000 monoterpenoid indole alkaloids (MIAs), including the anticancer drug vinblastine, involves the highly unstable intermediate strictosidine aglycone. Its formation by strictosidine {beta}-glucosidase (SGD) and subsequent conversion by geissoschizine synthase (GS) occur in spatially separated compartments, representing a major biosynthesis bottleneck. Here we discover VinBLAST, a cinnamyl alcohol dehydrogenase-like protein repurposed as a scaffold for efficient processing of this labile intermediate. VinBLAST physically mediates SGD and GS interaction in the nucleus and allosterically enhances GS catalytic efficiency. VinBLAST homologues from diverse plant families enhance biosynthesis of several representative MIAs, with the production of catharanthine increased to ~160 mg L-1 in yeast, nearly 1,000-fold higher than previous studies. Our discovery provides a missing link in organizing MIA biosynthesis and enables scalable bioproduction of geissoschizine-derived therapeutics.

synthetic biology↗

lncRNA MANCR isoforms selectively mediate multiple levels of epigenomic and P53-responsive transcriptional control in triple negative breast cancer

Long noncoding RNAs (lncRNAs) are important regulators of gene expression and are frequently dysregulated in cancer. The mitotically associated lncRNA MANCR is highly expressed in aggressive cancers and contributes to genomic instability in triple-negative breast cancer (TNBC), but the molecular mechanisms underlying its activity remain poorly defined. Here we integrate computational and experimental approaches to examine the structure and regulatory interactions of MANCR isoforms. Analysis of transcriptomic datasets revealed tumor-type-specific expression patterns for seven MANCR isoforms in breast cancer cell lines. Computational prediction of RNA secondary structures identified conserved structural features across isoforms, suggesting potential functional specialization. We identify p53 as a MANCR-interacting protein through computational docking and RNA immunoprecipitation sequencing (RIP-seq) and demonstrate that MANCR depletion reduces p53-dependent transcriptional activity. Chromatin isolation by RNA purification sequencing (ChIRP-seq) revealed 1, 250 genomic regions associated with MANCR, including enrichment of p53 consensus motifs and GC-rich sequence elements. Motif analysis further identified candidate sequence features associated with MANCR-occupied chromatin regions. Computational prediction of RNA-miRNA interactions identified multiple potential miRNA binding sites across MANCR isoforms, including miR-6756-5p, which targets the androgen receptor (AR). Consistent with this prediction, AR expression decreased following MANCR knockdown in TNBC cells. Together, these results suggest that MANCR isoforms may contribute to transcriptional regulation in TNBC through interactions with chromatin, p53 signaling pathways, and potential miRNA regulatory networks. One Sentence SummaryMitotically-associated lncRNA (MANCR) is prevalent in aggressive cancers interacting with DNA, P53, and miRNAs, to mediate multiple levels of epigenetic transcriptional control in triple negative breast cancer.

cancer biology↗

Exploring Chromosomal Position Effects for Predictable Tuning of Metabolic Pathways in Yeast

Precise control of gene expression is essential for optimizing metabolic pathways, yet current tuning strategies based on promoter strength or gene copy number remain largely empirical. Chromosomal position represents an additional regulatory axis, as identical gene expression cassettes can exhibit markedly different expression levels depending on their integration sites. Here, we systematically quantified the expression output of 98 intergenic regions (IGRs) in Saccharomyces cerevisiae using a fluorescent reporter and developed a predictive framework, Yeast IGR Prophet (YeIP), that infers expression potential directly from genomic context. By integrating multi-scale genomic features including transcriptional neighborhood, chromatin state, and chromosome topology, YeIP accurately predicted expression ranks and enabled the construction of a genome-wide atlas of expression hotspot and coldspot. Using this atlas, we rationally optimized a three-gene lycopene pathway solely through genomic integration site selection, achieving optimal transcriptional stoichiometry without modifying promoters or gene copy numbers. These results transform chromosomal integration sites from static genomic coordinates into programmable regulatory elements, establishing a predictive, data-driven framework for rational and scalable design of metabolic pathways in yeast.

synthetic biology↗

Acute degron-mediated RUNX1 loss reprograms enhancer activity to epigenetically drive epithelial destabilization and initiate cancer hallmarks

The RUNX1 transcription factor mediates cell-type specific gene expression. RUNX1 suppression and perturbations are recurrently associated with breast tumor initiation and progression. However, the mechanisms governing the dual roles of RUNX1 in sustaining the mammary epithelial phenotype while epigenetically suppressing initiation of cancer-compromised gene expression are poorly understood. To address this, we used the power of degron-mediated acute, selective, and complete RUNX1 ablation in human mammary epithelial cells. RUNX1 mediates promoter and distal enhancer-driven expression of a gene cohort. Dynamic epigenomic responsiveness upon RUNX1 ablation reveals a rapid and selective decrease in chromatin accessibility and H3K27ac at RUNX1-bound enhancers, but not promoters. While differentially initiated and expressed genes contacted by RUNX1-bound enhancers are enriched in pathways involved in epithelial maintenance and stemness, genes with RUNX1-promoter occupancy support DNA damage responsiveness. Modified cell morphology, metabolic control, increased breast cancer stemness, plasticity, anchorage-independent survival, chemoresistance, and perturbed DNA damage reactivity are observed upon RUNX1 ablation. Together, these findings define RUNX1 as an epigenetic tumor suppressor that maintains epithelial cell state by preserving enhancer activity and preventing gene expression associated with hallmarks of cancer.

cancer biology↗

MRN-ATM Pathway Activation in CD4 T-Cell Senescence during Chronic Hepatitis B Virus Infection

T-cell senescence is a hallmark of immune dysfunction in persistent viral infections, characterized by DNA damage accumulation and telomere erosion. However, the mechanisms driving CD4 T-cell senescence in the context of chronic hepatitis B virus (HBV) infection remain poorly defined. In this study, we demonstrated that people with chronic HBV infection exhibited CD4 T-cell senescence, marked by elevated KLRG1, along with increased DNA damage and telomere shortening, compared to HS. Notably, activation of the MRN-ATM (MRE11/RAD50/NBS1-Ataxia Telangiectasia Mutated Protein) pathway was prominent in CD4 T cells from HBV patients. Importantly, suppression of MRN attenuated ATM phosphorylation and its downstream signaling molecules, and inhibition of ATM reduced the production of proinflammatory cytokines in CD4 T cells derived from both HBV patients and HS. These results suggest that in chronic HBV infection, the virus induced CD4 T-cell senescence, telomere erosion, and DNA damage, while concurrent activation of the MRN-ATM pathway may serve as a compensatory mechanism to preserve CD4 T-cell function. Elucidating this relationship between T-cell senescence and DNA damage repair helps to understanding the mechanisms underlying HBV persistence and providing potential therapeutic targets against chronic HBV infection.

immunology↗

A novel dephosphorylation peptide inhibits 17β-HSD1 enzyme activity in ovarian granulosa cells and breast cancer cells

Estradiol (E2), a pivotal mammalian reproductive hormone, is closely associated with estrogen-dependent diseases. 17{beta}-hydroxysteroid dehydrogenase type 1 (17{beta}-HSD1), a critical E2 synthesis enzyme, has been understudied for its post-translational regulation-despite its potential as a therapeutic target, no clinically approved inhibitors are currently available. In our investigation of porcine follicular atresia mechanisms, we identified five differentially phosphorylated residues in 17{beta}-HSD1. Using in vitro site-directed mutagenesis and transgenic mouse models carrying point mutations, we established that Ser30 and Ser274 are critical phosphorylation sites that robustly modulate 17{beta}-HSD1 enzymatic activity. We further demonstrated that activin A and insulin-like growth factor 1 (IGF-1) enhance 17{beta}-HSD1 activity by promoting its phosphorylation at these two sites. To target these regulatory residues, we designed and synthesized cell-penetrating peptides (CPPs) that specifically suppress 17{beta}-HSD1 phosphorylation. Functional assays conclusively demonstrated that these CPPs significantly suppressed 17{beta}-HSD1 activity in vitro. Notably, they also inhibited the proliferation, migration and invasion of MCF-7 cells, as well as tumor growth in a mouse model of breast cancer. Our study provides novel mechanistic insights into the regulation of 17{beta}-HSD1 and E2 synthesis, addressing a critical gap in steroid hormone biology. The identification of Ser30/Ser274 as functional phosphorylation sites and the development of CPP-based inhibitors offer both theoretical advances and translational potential, opening new avenues for the treatment of estrogen-dependent breast cancer.

cell biology↗

Geographical variation drives adaptive equilibrium of the P. falciparum sickle-associated mutations

The recent discovery of genetic mutations in Plasmodium falciparum--the most lethal malaria parasite--that enable it to overcome the protective effects of sickle cell trait, raises fundamental questions about the underlying biological and evolutionary interactions. Here we develop a geostatistical model to compare sickle haemoglobin genotype frequencies to the Plasmodium falciparum sickle-associated alleles across global populations, and find a robust association at multiple geographical scales, implying that sickle drives positive selection for these parasite mutations. A model of parasite evolution and an analysis of local haplotype patterns suggest that key features of these mutations - that they are polymorphic in all African populations and are mutually correlated despite lying in different genome regions - are caused by geographical variation in selection pressure, and that the alleles may have been maintained by balancing selection over timescales comparable to the age of the sickle mutation itself. The predicted impact of this host-parasite interaction on disease outcomes varies widely across populations, and functional data are needed to discover the biological mechanisms involved.

genetics↗

Lineage-Specific Epigenomic Mapping of Proximal and Distal Fallopian Tube Epithelium Reveals Mesenchymal/Wnt-Driven Tumor Phenotype Diversification

High-grade serous ovarian cancer (HGSC) typically originates from the distal fallopian tube epithelium (disFTE), while the proximal epithelium (proFTE) remains less explored. Here, Using isogenic murine organoid models with common oncogenic drivers (Tp53-/-; Krasmut; Pten-/-), we show that disFTE and proFTE generate distinct tumor subtypes driven by region-specific transcriptional programs. Unlike disFTE, proFTE demonstrates continuous activation of epithelial-mesenchymal transition (EMT) across wild-type, mutant organoids, and derived tumors. Additionally, mutated proFTE organoids and their tumors exhibit persistent WNT signaling activation and grow independently of WNT signals. Chromatin profiling shows that mutant proFTE maintains a distinctive epigenetic profile with promoters associated with EMT and WNT pathways. Human proFTE with BRCAmut also shows epigenetic activation of EMT- and WNT-related genes. Tumors near the uterotubal junction (UTJ)--anatomically akin to proFTE--exhibit a pronounced EMT signature, increased Vimentin+E-cadherin+ and nuclear {beta}-catenin expression. These findings suggest proFTE-derived tumors may occupy a unique niche in gynecological malignancies, with regional identity shaping tumor phenotypes.

cancer biology↗

The Polymorphism of Globin and Virus RdRP and Protein Space

The divergence of protein sequences, structures, and functions reveals Natures exploration of evolutionary possibilities within a given structural fold. Globins are ubiquitous across bacteria, fungi, plants, and animals; RNA-dependent RNA polymerases (RdRPs) are responsible for the replication of RNA viruses. These proteins provide excellent models for the study of protein evolution. In this study we analyzed the polymorhpisms of globins and viruses RdRPs with structure and function. We found that the protein polymorphisms are positively correlated with residue solvent accessibility (RSA). From our analysis of protein space of globins and virus RdRPs, we proposed that purifying selection is the predominant force of protein evolution. We also discuss the theory of last universal common ancestor (LUCA), proposed that it may be put to test.

bioinformatics↗

Polymorphisms, Solvent Accessibility, and Evolutionary Conservation of Influenza A Virus PB1 Protein

Protein polymorphisms, reflecting amino acid and nucleotide sequence divergence, provide insights into protein evolution. Here, we analyze sequence variation and structural features of influenza A virus (IAV) PB1 protein, an RNA-dependent RNA polymerase critical for viral replication. Our findings demonstrate that residue solvent accessibility strongly predicts polymorphism likelihood, with exposed sites exhibiting higher variability. Despite extensive polymorphism, we observe pervasive purifying selection across PB1, maintaining functional and structural constraints. These results highlight how protein architecture shapes evolutionary dynamics in viral proteins.

bioinformatics↗

Elucidation and de novo Reconstitution of Glyceollins Biosynthesis

Glyceollins are phytoalexins produced by soybeans in response to stressors such as pathogen invasion, injury, and environmental challenges. In addition to their antibacterial and antifungal activities, these compounds have attracted significant attention for their potential anticancer, anti-inflammatory, and antioxidant properties. However, their limited accessibility--due to the challenges and high costs associated with organic synthesis or purification from treated soybean seedlings--has hindered further physiological and biochemical studies. Moreover, the incomplete understanding of glyceollin biosynthesis, particularly the final cyclization steps, remains a major barrier to elucidating the physiological functions of glyceollins and achieving sustainable production through synthetic biology. In this study, we identified previously uncharacterized genes encoding two reductases for 7,2,4-trihydroxyisoflavanol (THI) biosynthesis and five P450 enzymes responsible for the final oxidative cyclization in glyceollin I, II, and III biosynthesis, thereby completing the entire glyceollin biosynthetic pathway. By reconstructing the pathway de novo through synthetic biology, we achieved the successful production of glyceollins from simple carbon sources in bakers yeast. This work advances the understanding of glyceollin biosynthesis in soybean, facilitates sustainable production in microbial hosts and offers new opportunities for their application in agriculture and biology.

biochemistry↗

Molecular sorting of nitrogenase catalytic cofactors

The free-living diazotroph Azotobacter vinelandii produces three genetically distinct but functionally and mechanistically similar nitrogenase isozymes, designated as Mo-dependent, V-dependent, and Fe-only. They respectively harbor nearly identical catalytic cofactors that are distinguished by a heterometal site occupied by Mo (FeMo-cofactor), V (FeV-cofactor), or Fe (FeFe-cofactor). Completion of FeMo-cofactor and FeV-cofactor formation occurs on molecular scaffolds prior to delivery to their catalytic partners. In contrast, completion of FeFe-cofactor assembly occurs directly within its cognate catalytic partner. Because hybrid nitrogenase species that contain the incorrect cofactor type cannot reduce N2 to support diazotrophic growth there must be a way to prevent misincorporation of an incorrect cofactor when different nitrogenase isozyme systems are produced at the same time. Here, we show that fidelity of the Fe-only nitrogenase is preserved by blocking the misincorporation of either FeMo-cofactor or FeV-cofactor during its maturation. This protection is accomplished by a two-domain protein, designated AnfO. It is shown that the N-terminal domain of AnfO binds to an immature form of the Fe-only nitrogenase and the C-terminal domain, tethered to the N-terminal domain by a flexible linker, has the capacity to capture FeMo- and FeV-cofactor. AnfO does not prevent the normal activation of Fe-only nitrogenase because completion of FeFe-cofactor assembly occurs within its catalytic partner and, therefore, is never available for capture by AnfO. These results support a post-translational mechanism involving the molecular sorting of structurally similar metallocofactors that involve both protein-protein interactions and metallocofactor binding while exploiting differential pathways for nitrogenase associated catalytic cofactor assembly.

biochemistry↗

Ancient gene clusters initiate monoterpene indole alkaloid biosynthesis and C-3 stereochemistry inversion

The inversion of C3 stereochemistry in monoterpenoid indole alkaloids (MIAs), derived from the central precursor strictosidine (3S), is a critical step for the biosynthesis of numerous 3R MIAs and spirooxindoles, including the antihypertensive drug reserpine. While early MIA biosynthesis preserves the 3S configuration, the mechanism underlying C3 inversion has remained unresolved. Here, we identify and biochemically characterize a conserved oxidase-reductase pair in the Gentianales order: the heteroyohimbine/yohimbine/corynanthe C3-oxidase (HYC3O) and C3-reductase (HYC3R), which together invert the 3S stereochemistry to 3R across diverse substrates. Notably, HYC3O and HYC3R reside in gene clusters in Rauvolfia tetraphylla and Catharanthus roseus, homologous to an elusive geissoschizine synthase (GS) cluster we also uncovered. In R. tetraphylla, these clusters are in tandem on a single chromosome, likely derived from segmental duplication, whereas in C. roseus they reside on separate chromosomes due to translocation. Comparative genomics indicate the GS cluster originated at the base of Gentianales ([~]135 Mya), coinciding with the evolution of the strictosidine synthase cluster, while the reserpine cluster arose later in rauvolfioid Apocynaceae. Together, these findings uncover the genomic and biochemical basis for key events in MIA evolution and diversification, providing insights beyond the canonical vinblastine and ajmaline biosynthetic pathways.

biochemistry↗

Latitudinal scaling of aggregation with abundance and its consequences for coexistence in species rich forests

The search for simple principles underlying the complex spatial structure and dynamics of plant communities is a long-standing challenge in ecology1-6. In particular, the relationship between the spatial distribution of plants and species coexistence is challenging to resolve in species-rich communities7-9. Analysing the spatial patterns of tree species in 21 large forest plots, we find that rare species tend to be more spatially aggregated than common species, and a latitudinal gradient in the strength of this negative correlations that increases from tropical to temperate forests. Our analysis suggests that latitudinal gradients in animal seed dispersal10 and mycorrhizal associations11,12,13 may jointly generate this intriguing pattern. To assess the consequences of negative aggregation-abundance correlations for species coexistence, we present here a framework to incorporate the observed spatial patterns into population models8 along with an analytical solution for the local extinction risk14 of species invading from low abundances in dependence of spatial structure, demographic parameters, and immigration. For example, the stabilizing effect of the observed spatial patterns reduced the local extinction risk of species when rare almost by a factor of two. Our approach opens up new avenues for integrating observed spatial patterns into mathematical theory, and our findings demonstrate that spatial patterns, such as species aggregation and segregation, can contribute substantially to coexistence in species-rich communities. This underscores the need to understand the interactions between multiple ecological processes and spatial patterns in greater detail.

ecology↗

Latitude influences stability via stabilizing mechanisms in naturally-assembled forest ecosystems at different spatial grains

Ecosystem stability reveals how ecosystems respond to global change over time. Yet, the focus of past research on small spatial grains and extents overlooks scale dependence and how broad-scale environmental gradients shape stability. Here, we use forest inventory data covering a broad latitudinal gradient from the temperate to the tropical zone to examine cross-scale variation in stability of aboveground biomass and underlying stabilizing mechanisms. While stability did not shift systematically with latitude at either spatial grain, we found evidence that species asynchrony increased towards the tropics at the small spatial grain while species stability decreased at both spatial grains. Moreover, latitude stabilized forest communities via its effects on both stabilizing mechanisms, which compensated for the weak and destabilizing effects of species richness. Yet, the trade-off in the relative importance of species stability and species asynchrony for stability was not mediated by latitude, suggesting that context-dependent factors - to a greater extent than macroecological ones - underlie large-scale patterns of stability. Our results highlight the crucial role of species asynchrony and species stability in determining ecosystem stability across broad-scale environmental gradients, suggesting that conserving biodiversity alone may not be sufficient for stabilizing naturally-assembled forest ecosystems.

ecology↗

Diversity and biogeography of plant leaf bacteria along a latitudinal gradient

Plant-associated microbes are essential for promoting plant well-being, maintaining biodiversity, and supporting ecosystem function. However, little is known about the geographic distribution of plant-microbe symbioses and how they are formed and change along latitudinal gradients. Here we identified leaf bacteria for 328 plant species sampled from 10 forests along a tropical to temperate gradient in China. We analyzed the diversity and composition of plant leaf-associated bacteria and quantified the contributions of hosts, habitats, and neighborhood plants to the plant-bacterial symbiosis. We found a strong latitudinal gradient in leaf bacterial diversity and composition. Bacterial assemblages on leaves were most strongly selected by host plants, and the selection pressure increased with latitude. In contrast, at low latitudes and at large geographical scales multiple factors were found to jointly regulate bacterial community composition. Our result also showed that plant-bacteria symbiotic networks were structured by network hub bacteria taxa with high co-occurrence network centrality, and the abundance of temperate hub taxa was more influenced by host plants than that in tropical forests. For the first time, we documented a previously unrecognized latitudinal gradient in plant-bacterial symbioses that was regulated by a joint effect of multiple factors at low latitudes but mostly by host selection at high latitudes, implying that leaf microbiomes are likely to respond differently to global change along the latitudinal gradient.

ecology↗