Biology subjects

Lin, J. Q.

Publications and source records attributed to Lin, J. Q..

9 recordsLinked to original sources

bioRxiv2026

Multiscale transcriptomic organization of the human brain with DigitalBrain

The human brain varies across anatomical regions, cell types, development, aging and disease states, yet existing single-cell transcriptomic resources remain fragmented and difficult to integrate into a unified biological model. Here we present DigitalBrain, a human brain-specific atlas and foundation-model framework for organizing diverse and fragmented human brain transcriptomic data across scales. We first built DigitalBrain-Atlas, a harmonized whole-brain single-cell resource comprising 16.35 million transcriptomes from 2,143 donors across 165 brain regions, spanning the human lifespan and multiple neurological and clinical conditions. We then developed DigitalBrain-M1, a Transformer-based model that jointly encodes gene identity and expression magnitude to learn a shared embedding space for cells and genes. Across held-out datasets, DigitalBrain supported robust single-cell integration, clustering and cell-type annotation while preserving major biological structure and reducing technical fragmentation. Beyond these benchmarks, the learned embeddings revealed emergent large-scale hierarchical organization of the human brain, linking anatomically distinct regions into higher-order patterns consistent with known functional systems. Applied to human hippocampal aging, DigitalBrain identified cell-type-specific aging sensitive gene sets, highlighted dentate gyrus granule cells as a particularly age-sensitive population, and discovered selective reorganization of gene programs related to synaptic transmission, postsynaptic structure, membrane excitability and axon guidance during aging. Cross-dataset convergence was strongest at the level of functional modules and recurrent aging sensitive genes. Together, these results demonstrate that DigitalBrain is a brain-specific framework for mapping human brain organization across scales, and as an early step towards a complete virtual organ for the human brain.

bioinformatics↗

bioRxiv2026

Cooperative and competitive interactions among transcription regulatory elements modulate transcription output

Transcription is modulated by interactions among transcription regulatory elements (TREs), including promoters and enhancers, but their underlying interaction specificities remain opaque. Here, we develop a Chromatin-Integrated, landing-pad-based Enhancer Reporter Assay, CIERA-seq, that interrogates regulatory interactions between target promoters and distal TREs in a controlled genomic and chromatin context. We find both promoter- and enhancer-TREs exhibit enhancer activities on target promoters with a specificity that depends on factors that TREs recruit. Promoters are generally enriched for factors involved in the core transcription process, whereas enhancers are enriched for pioneer factors and chromatin remodelers. Our CIERA-seq assays support a model where TREs activate target promoters constrained at different rate limiting steps in transcription by supplying complementary components of the transcription regulatory machinery. An orthogonal analysis using CRISPRi datasets shows that both promoters and enhancers can positively regulate expression of neighboring genes at their native loci. However, promoters are also more prone than enhancers to exhibit negative regulatory effects, a difference that may arise from competition for limiting transcriptional machinery. Together, these findings support a framework in which promoters and enhancers act as cooperative, or competitive, regulatory elements within local transcription hubs to modulate transcription outputs.

molecular biology↗

bioRxiv2025

RNA secondary structures modulate hnRNPH1-mediated alternative splicing of cold-shock protein RBM3

Alternative splicing is regulated not only by sequence-specific RNA-protein interactions, but also by dynamic RNA secondary structures that remodel under varying cellular conditions. hnRNPH1, a G-rich motif-binding protein, promotes exon skipping across numerous transcripts, yet how RNA structure shapes its regulatory activity remains unclear. Building on our previous work showing that cooler temperature enhances hnRNPH1 binding to RBM3 pre-mRNA and drives poison exon (PE) skipping, we now identify RNA G-quadruplex (rG4) remodelling as the principal cis-acting mechanism underlying this temperature-sensitive regulation. Using small-molecule stabilizers and destabilizers, we show that rG4 folding reduces PE skipping, whereas rG4 destabilization enhances hnRNPH1-mediated PE exclusion. These effects are conserved across neuronal and non-neuronal cells. Integrating proteomics, phosphoproteomics, kinase perturbation assays, and candidates emerging from our prior genome-wide CRISPR screen, we further uncover contributions from temperature-sensitive CDC2-like kinase signalling and the RNA helicase DDX5, a known rG4 resolver and an hnRNPH1/hnRNPF co-factor. Together, our findings establish rG4 remodelling as the dominant driver of hnRNPH1-dependent RBM3 splicing, while implicating helicase activity and kinase signalling as modulatory layers that fine-tune this response. More broadly, this work illustrates how environmentally driven RNA structural transitions interface with enzymatic regulators to achieve temperature-responsive control of alternative splicing.

molecular biology↗

bioRxiv2024

In Situ Integration of Porous Polyethylene Nanomembrane with Wound Exudates for Scarless Healing

Achieving scarless wound repair through innovative material designs, such as hydrogels infused with growth factors and cells, has been extensively explored. In this study, we introduce a scarless healing material called pgPE, which is based on a porous and biologically inert ultra-high molecular weight polyethylene (UHMWPE) nanomembrane. This highly flexible nanomembrane conforms closely to the wound site and effectively absorbs wound-associated species into its nanopores, forming pgPE in situ. The resulting pgPE creates an ideal environment that fosters physiological metabolism while acting as a barrier against pathogens. Our findings demonstrate that pgPE facilitates complete skin reconstruction, including the regeneration of hair follicles. Additionally, we characterized the immune microenvironment and hypoxic conditions, revealing that pgPE alleviates hypoxia and modulates immune responses, thereby promoting healing towards a scar-free outcome. The integration of wound-associated species within pgPE has been evidenced through three-dimensional Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) analysis of postmortem samples. This study highlights the potential of personalized solutions that align with physiological systems for enhanced wound healing.

bioengineering↗

bioRxiv2022

HNRNPH1 regulates the neuroprotective cold-shock protein RBM3 expression through poison exon exclusion

Enhanced expression of the cold-shock protein RNA binding motif 3 (RBM3) is highly neuroprotective both in vitro and in vivo. Whilst upstream signalling pathways leading to RBM3 expression have been described, the precise molecular mechanism of RBM3 induction during cooling remains elusive. To identify temperature-dependent modulators of RBM3, we performed a genome-wide CRISPR-Cas9 knockout screen using RBM3-reporter human iPSC-derived neurons. We found that RBM3 mRNA and protein levels are robustly regulated by several splicing factors, with heterogeneous nuclear ribonucleoprotein H1 (HNRNPH1) being the strongest positive regulator. Splicing analysis revealed that moderate hypothermia significantly represses the inclusion of a poison exon, which, when retained, targets the mRNA for nonsense-mediated decay. Importantly, we show that HNRNPH1 mediates this cold-dependent exon skipping via its interaction with a G-rich motif within the poison exon. Our study provides novel mechanistic insights into the regulation of RBM3 and provides further targets for neuroprotective therapeutic strategies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/514062v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@ef0a5org.highwire.dtl.DTLVardef@d907a5org.highwire.dtl.DTLVardef@85176aorg.highwire.dtl.DTLVardef@1c4306a_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2022

Mutation of the ALS/FTD-associated RNA-binding protein FUS alters axonal cytoskeletal organisation

Aberrant condensation and localisation of the RNA-binding protein fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ALS is also associated with cytoskeletal defects, genetically and through observations of compromised axonal transport. Here, we asked whether compromised axonal cytoskeletal organisation is an early feature of FUS-associated ALS/FTD. We used an ALS-associated mutant FUS(P525L) and the FTD-mimic hypomethylated FUS, FUS(16R), to investigate the common and distinct cytoskeletal changes found in these two reported Xenopus models. Combining a novel atomic force microscopy (AFM)-based approach for in vitro cytoskeletal characterisation and in vivo axonal branching analysis, we found that mutant FUS reduced actin density in the dynamically remodelling growth cone, and reduced axonal branch complexity. We furthermore found evidence of an axon looping defect for FUS(P525L). Therefore, we show that compromised actin remodelling is potentially an important early event in FUS-associated pathogenesis. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/510780v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@1e9a92aorg.highwire.dtl.DTLVardef@161076eorg.highwire.dtl.DTLVardef@12edf0forg.highwire.dtl.DTLVardef@365785_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Xenogeneic Skin Transplantation Promotes Angiogenesis and Tissue Regeneration Through Vitamin D-Activated Trem2+ Macrophages

Skin allo- and xenotransplantation are the standard treatment for major burns when donor sites for autografts are not available and have been shown to significantly accelerate wound healing. Although the cellular elements of foreign grafts are rejected, the extracellular matrix components integrate into the wound and may underlie their beneficial effects on wound healing. The molecular mechanisms defining the relationship between the immune response to foreign grafts and their impact on wound healing have not been fully elucidated. Here, we investigated changes in collagen architecture after xenogeneic implantation of clinically available human biologic scaffolds. We show that collagen deposition in response to the implantation of human split-thickness skin grafts (hSTSG) containing live cells recapitulates normal skin architecture, whereas human acellular dermal matrix (ADM) grafts led to highly aligned collagen deposition, characteristic of fibrosis and scar. Using single-cell RNA-sequencing, we show that macrophage differentiation in response to hSTSG is driven by vitamin D (VD) signaling toward Trem2+ subpopulations with an enrichment of pro-angiogenic and anti-fibrotic transcriptomic programs. We subsequently induced this regenerative subpopulation in vitro by treating bone marrow-derived cells with vitamin D3 and found that hydrogel delivery of Trem2+ macrophages significantly accelerated wound closure in a human-like murine excisional wound model. Our study identifies the preclinical therapeutic potential of Trem2+ macrophages to mitigate fibrosis and promote wound healing and provides a novel effective strategy to develop advanced cell therapies for complex wounds. One Sentence SummaryVitamin D-activated Trem2+ macrophages promote angiogenesis and mitigate fibrosis, providing a novel effective strategy to develop advanced cell therapies for complex wounds.

immunology↗

bioRxiv2019

A waveguide imaging platform for live-cell TIRF imaging of neurons over large fields of view

Large fields of view (FOVs) in total internal reflection fluorescence microscopy (TIRFM) via waveguides have been shown to be highly beneficial for single molecule localisation microscopy on fixed cells [1, 2] and have also been demonstrated for short-term live-imaging of robust cell types [3-5], but not yet for delicate primary neurons nor over extended periods of time. Here, we present a waveguide-based TIRFM set-up for live-cell imaging of demanding samples. Using the developed microscope, referred to as the ChipScope, we demonstrate successful culturing and imaging of fibroblasts, primary rat hippocampal neurons and axons of Xenopus retinal ganglion cells (RGC). The high contrast and gentle illumination mode provided by TIRFM coupled with the exceptionally large excitation areas and superior illumination homogeneity offered by photonic waveguides have potential for a wide application span in neuroscience applications.

neuroscience↗

bioRxiv2018

On-site ribosome remodeling by locally synthesized ribosomal proteins in axons

Ribosomes are known to be assembled in the nucleolus, yet recent studies have revealed robust enrichment and translation of mRNAs encoding ribosomal proteins (RPs) in axons, far away from neuronal cell bodies. Using subcellular proteomics and live-imaging, we show that locally synthesized RPs incorporate into axonal ribosomes in a nucleolus-independent fashion. We revealed that axonal RP translation is regulated through a novel sequence motif, CUIC, that forms a RNA-loop structure in the region immediately upstream of the initiation codon. Inhibition of axonal CUIC-regulated RP translation leads to defects in local translation activity and axon branching, demonstrating the physiological relevance of the axonal ribosome remodeling. These results indicate that axonal translation supplies cytoplasmic RPs to maintain/modify local ribosomal function far from the nucleolus.

neuroscience↗