Biology subjects

Sun, Y.-C.

Publications and source records attributed to Sun, Y.-C..

10 recordsLinked to original sources

bioRxiv2025

Exploring multi-level microbial interactions from individual 3D genomes to community networks

Microbial communities interact with their hosts through complex genomic networks that influence ecosystem stability and disease progression. Here, we present FindMeta3D, a computational framework that simultaneously identifies microbial three-dimensional (3D) genome structures and cross-domain interaction networks. Applying this approach to 528 Hi-C samples, we resolved 3D genome structures of 344 microbial species, revealing five evolutionarily conserved chromatin folding patterns linked to intrinsic sequence features. Further analyses demonstrated distinct microbial-host interaction preferences and identified functional interaction hotspots that are critical for infection. Experimental deletion of such hotspots in the EBV genome resulted in significant infection defects, demonstrating their essential role in viral infectivity. Additionally, we constructed the first Cross-domain Microbial Interaction Network (CMIN), which uncovered pathogen-specific subnetworks and demonstrate dramatic restructuring of gut microbial communities in neutropenic patients, including enhanced Klebsiella-phage interactions. Subnetwork analysis identified potential phage therapy targets, such as Klebsiella phage ST16-OXA48phi5.4. These findings provide fundamental insights into microbial 3D genomics and establish FindMeta3D as a powerful platform for studying microbial genome structure and communities and developing antimicrobial strategies.

microbiology↗

bioRxiv2025

Protein large language model assisted one-to-one gene homology mapping in cross-species single-cell transcriptome integration

Cross-species integration of single-cell transcriptomes requires establishing gene correspondences to enable comparative analysis of expression profiles across organisms. Current approaches predominantly rely on Ensembl homology tables; although gene-family expansion and contraction can reflect biologically meaningful evolutionary divergence, default many-to-many mappings can overweight expanded gene-family signals during integration and generate mapping-associated micro-clusters that lack clear cell-type identity, thereby complicating direct cell-type alignment. While restricting mappings to a one-to-one scheme suppresses such artifacts, it reduces the number of homology gene pairs by approximately 8% ([~]900 pairs). To address this limitation, we develop a protein large language model (pLLM)-based gene homology mapping strategy that boosts the number of homology gene pairs. By integrating pLLM-derived representations with sequence similarity, we construct a fused mapping approach, which achieves top performance in a comprehensive benchmark based on a curated cross-species atlas--spanning nine datasets, 11 species, and over 3.2 million cells. Our method further identifies previously unannotated cell-type marker pairs, facilitating novel cross-species marker discovery. These results establish a robust framework for gene homology mapping in cross-species transcriptome integration, improving both accuracy and biological interpretability.

bioinformatics↗

bioRxiv2025

Hi-Compass resolves cell-type chromatin interactions by single-cell and spatial ATAC-seq data across biological scales

Computational prediction of three-dimensional (3D) genome organization provides an alternative approach to overcome the cost and technical limitations of Hi-C experiments. However, current Hi-C prediction models are constrained by their narrow applicability to studying the impact of genetic variation on genome folding in specific cell lines, significantly restricting their biological utility. We present Hi-Compass, a generalizable deep learning model that accurately predicts chromatin organization across diverse biological contexts, from bulk to single-cell samples. Hi-Compass outperforms existing methods in prediction accuracy and is generalizable to unseen cell types through chromatin accessibility data, enabling broad applications in single cell omics. Hi-Compass successfully resolves cell-type-specific 3D genome architectures in complex biological scenarios, including immune cell states, organ heterogeneity, and tissue spatial organization. Furthermore, Hi-Compass enables integrative analysis of single-cell multiome data, linking chromatin interaction dynamics to gene expression changes across cell clusters, and mapping disease variants to pathogenic genes. Hi-Compass also extends to spatial multi-omics data, generating spatially resolved Hi-C maps that reveal domain-specific chromatin interactions linked to spatial gene expression patterns.

bioinformatics↗

bioRxiv2025

The Mycobacterium tuberculosis ESX effector promotes pyroptosis-dependent pathogenicity and dissemination

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/653593v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@8cd5e5org.highwire.dtl.DTLVardef@2ec22forg.highwire.dtl.DTLVardef@1ceb773org.highwire.dtl.DTLVardef@6dfba4_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphic AbstractC_FLOATNO C_FIG Mycobacterium tuberculosis (Mtb) remains a major global health threat, partly due to the extensive cytotoxicity induced during infection. Although GSDMD-mediated excessive pyroptosis promotes pathogen dissemination and tissue damage in tuberculosis, the mechanism remains poorly understood. Here, we identify the effector EccB5, a component of the Mtb ESX-5 secretion system, as a key driver of pyroptosis and hyperinflammatory responses. EccB5 enhances Mtb virulence by inducing pyroptosis of macrophages, promoting bacterial dissemination and exacerbating lung pathology. Conditional knockdown EccB5 increases host cell viability. Mechanistically, EccB5 directly interacts with GSDMD, strengthens its association with caspase-1, and facilitates caspase-1-mediated cleavage of GSDMD both in vitro and in vivo. In summary, our findings uncover a precise mechanism by which Mtb modulates host responses and advances its pathogenicity.

microbiology↗

bioRxiv2025

ACE2 utilization of HKU25 clade MERS-related coronaviruses with broad geographic distribution

Dipeptidyl peptidase-4 (DPP4) is a well-established receptor for several MERS-related coronaviruses (MERSr-CoVs) isolated from humans, camels, pangolins, and bats (1-6). However, the receptor usage of many genetically diverse bat MERSr-CoVs with broad geographical distributions remains poorly understood. Recent studies have identified angiotensin-converting enzyme 2 (ACE2) as an entry receptor for multiple merbecovirus clades. Here, using viral antigen and pseudovirus-based functional assays, we demonstrate that several bat merbecoviruses from the HKU25 clade previously thought to utilize DPP4 (7), employ ACE2 as their functional receptor. Cryo-electron microscopy analysis revealed that HsItaly2011 and VsCoV-a7 recognize ACE2 with a binding mode sharing similarity with that of HKU5 but involving remodeled interfaces and distinct ortholog selectivity, suggesting a common evolutionary origin of ACE2 utilization for these two clades of viruses. EjCoV-3, a strain closely related to the DPP4-using MERSr-CoV BtCoV-422, exhibited relatively broad ACE2 ortholog tropism and could utilize human ACE2 albeit suboptimally. Despite differences in entry mechanisms and spike proteolytic activation compared to MERS-CoV, these viruses remain sensitive to several broadly neutralizing antibodies and entry inhibitors. These findings redefine our understanding of the evolution of receptor usage among MERSr-CoVs and highlight the versatility of ACE2 as a functional receptor for diverse coronaviruses. SignificanceRecent studies unexpectedly revealed that several merbecoviruses convergently evolved ACE2 receptor usage with distinct binding modes across three continents, challenging the dogma that DPP4 is their primary receptor. Here, we demonstrate that HKU25 clade MERS-related coronaviruses broadly distributed across Eurasia utilize ACE2 as host receptor through a binding mode shared with HKU5, challenging prior findings. These findings reveal a prevalence of ACE2 usage in diverse MERS-related coronaviruses in bats and show that EjCoV-3 is preadapted to use human ACE2, suggesting a potential for spillover. Our data provide a blueprint of host receptor barrier determinants which will facilitate global surveillance and development of countermeasures against these poorly characterized merbecoviruses.

microbiology↗

bioRxiv2022

A frameshift in Yersinia pestis rcsD leads to expression of a small HPt variant that alters canonical Rcs signalling to preserve flea-mammal plague transmission cycles

Multiple genetic changes in the enteric pathogen Yersinia pseudotuberculosis have driven the emergence of Yesinia pestis, the arthropod-borne, etiological agent of plague. These include developing the capacity for biofilm-dependent blockage of the flea foregut to enable transmission by flea bite. Previously, we showed that pseudogenisation of rcsA, encoding a component of the Rcs signalling pathway, is an important evolutionary step facilitating Y. pestis flea-borne transmission. Additionally, rcsD, another important gene in the Rcs system, harbours a frameshift mutation. Here, we demonstrated that this rcsD mutation resulted in predominant production of a small protein composing the C-terminal RcsD histidine-phosphotransferase domain (designated RcsD-Hpt) and low levels of full-length RcsD. Genetic analysis revealed that the rcsD frameshift mutation followed the emergence of rcsA pseudogenisation. It further altered the canonical Rcs phosphorylation signal cascade, fine-tuning biofilm production to be conducive with retention of the pgm locus in modern lineages of Y. pestis. Taken together, our findings suggest that a frameshift mutation in rcsD, is an important evolutionary step that fine-tuned biofilm production to ensure perpetuation of flea-mammal plague transmission cycles.

microbiology↗

bioRxiv2022

Phase separation driven by interchangeable properties in the intrinsically disordered regions of protein paralogs

Paralogs, arising from gene duplications, increase the functional diversity of proteins. Protein functions in paralog families have been extensively studied, but little is known about the roles of intrinsically disordered regions (IDRs), even though more than half of eukaryotic proteins have them. Using the RNA-binding protein Musashi family as an example, we applied multiple structural techniques and phylogenetic analysis to show how members in a paralog family have evolved their IDRs to different physicochemical properties but converge to the same function. In this example, the lower prion-like tendency of Musashi-1s IDRs, rather than Musashi-2s, is compensated by its higher -helical propensity to assist their assembly. Without a folded structure to restraint, IDRs sequences mutate faster along with evolution. No matter how fast they change, our work suggests that IDRs evolve different traits to a converged function, such as liquid-liquid phase separation.

biophysics↗

bioRxiv2020

Integrating barcoded neuroanatomy with spatial transcriptional profiling reveals cadherin correlates of projections shared across the cortex

Functional circuits consist of neurons with diverse axonal projections and gene expression. Understanding the molecular signature of projections requires high-throughput interrogation of both gene expression and projections to multiple targets in the same cells at cellular resolution, which is difficult to achieve using current technology. Here, we introduce BARseq2, a technique that simultaneously maps projections and detects multiplexed gene expression by in situ sequencing. We determined the expression of cadherins and cell-type markers in 29,933 cells, and the projections of 3,164 cells in both the mouse motor cortex and auditory cortex. Associating gene expression and projections in 1,349 neurons revealed shared cadherin signatures of homologous projections across the two cortical areas. These cadherins were enriched across multiple branches of the transcriptomic taxonomy. By correlating multi-gene expression and projections to many targets in single neurons with high throughput, BARseq2 provides a path to uncovering the molecular logic underlying neuronal circuits.

neuroscience↗

bioRxiv2018

Spatial organization of projection neurons in the mouse auditory cortex identified by in situ barcode sequencing

Understanding neural circuits requires deciphering interactions among myriad cell types defined by spatial organization, connectivity, gene expression, and other properties. Resolving these cell types requires both single neuron resolution and high throughput, a challenging combination with conventional methods. Here we introduce BARseq, a multiplexed method based on RNA barcoding for mapping projections of thousands of spatially resolved neurons in a single brain, and relating those projections to other properties such as gene or Cre expression. Mapping the projections to 11 areas of 3579 neurons in mouse auditory cortex using BARseq confirmed the laminar organization of the three top classes (IT, PT-like and CT) of projection neurons. In depth analysis uncovered a novel projection type restricted almost exclusively to transcriptionally-defined subtypes of IT neurons. By bridging anatomical and transcriptomic approaches at cellular resolution with high throughput, BARseq can potentially uncover the organizing principles underlying the structure and formation of neural circuits.

neuroscience↗

bioRxiv2017

Efficient in situ barcode sequencing using padlock probe-based BaristaSeq

Cellular DNA/RNA tags (barcodes) allow for multiplexed cell lineage tracing and neuronal projection mapping with cellular resolution. Conventional approaches to reading out cellular barcodes trade off spatial resolution with throughput. Bulk sequencing achieves high throughput but sacrifices spatial resolution, whereas manual cell picking has low throughput. In situ sequencing could potentially achieve both high spatial resolution and high throughput, but current in situ sequencing techniques are inefficient at reading out cellular barcodes. Here we describe BaristaSeq, an optimization of a targeted, padlock probe-based technique for in situ barcode sequencing compatible with Illumina sequencing chemistry. BaristaSeq results in a five-fold increase in amplification efficiency, with a sequencing accuracy of at least 97%. BaristaSeq could be used for barcode-assisted lineage tracing, and to map long-range neuronal projections.\n\nKey PointsO_LIIn situ sequencing by gap-filling padlock probes is limited by the strand displacement of DNA polymerases\nC_LIO_LIIllumina sequencing chemistry offers superior signal-to-noise ratio in situ compared to sequencing by ligation\nC_LIO_LIBaristaSeq as an accurate method for barcode sequencing in situ with improved gap-filling efficiency\nC_LI

molecular biology↗