Biology subjects

Chen, D. C.

Publications and source records attributed to Chen, D. C..

6 recordsLinked to original sources

bioRxiv2026

Tumor-tropic E. coli engineered as living T and NK cell engagers

Despite advances in immunotherapy, most solid tumors remain resistant to treatment. Immune cell engagers redirect cytotoxic lymphocytes against cancer, but limited tumor access, immunosuppressive microenvironments and systemic immune activation limit efficacy. Here we develop live immune modulating engagers (LIME), a modular platform where non-pathogenic, tumor-tropic Escherichia coli display tandem single-chain variable fragments targeting a tumor-associated antigen and an activating receptor on T or natural killer cells. LIME bridged effector and tumor cells, induced transcriptional programs of T cell activation, metabolism and proliferation, and enhanced cytotoxicity across cancer cell lines and patient-derived organoids. In mouse models, LIME safely accumulated in tumors, outperformed tarlatamab in small cell lung cancer, and induced durable immunity in lymphoma. RAS inhibition and PD-L1 blockade enhanced LIME activity in pancreatic cancer and induced humoral responses. Multi-lineage immune modulation remained tumor-confined, without organ toxicity. These findings establish LIME as a versatile living therapeutic platform for programmable, tumor-restricted immune orchestration.

bioengineering↗

bioRxiv2025

Dissecting the epigenome dynamics in human immune cells upon viral and chemical exposure by multimodal single-cell profiling

Environmental and pathogen exposure can lead to profound remodeling of the gene-regulatory landscape across human immune cell populations. Here, we present a single-nucleus chromatin accessibility atlas of human immune cells comprising 271,299 cells and 319,420 candidate regulatory elements from individuals exposed to HIV-1, COVID-19, Influenza virus, organophosphates, as well as healthy controls. Our longitudinal HIV cohort reveals epigenetic signatures of T cell exhaustion manifested in changes in the accessibility at binding sites for the FOXP family transcription factors. Upon severe exposure to SARS-Cov2 we identified changes in chromatin accessibility manifesting in a regulatory switch in cytokine networks characterized by the downregulation of the NF-{kappa}B motif family, alongside concordant changes in AP-1 and IRF factor networks in CD14+ classical monocytes. By integrating single-cell profiles of DNA methylation from matched samples, we created a multimodal epigenome atlas of human immune cell states using the accessibility-derived candidate regulatory elements. Both modalities exhibit complementary epigenetic signatures at transcription factor binding sites associated with cell state, as exemplified in the process of memory formation in T-cells, where BATF, AP-1, and ETS motifs exhibit significant epigenetic covariance across both epigenomic layers. Finally, by linking potentially regulatory DNA methylation signatures to changes in chromatin accessibility in monocytes, we observe that severe COVID-19 involves selective, multiomics remodeling of epigenetic profiles at TF binding sites manifested in concordant DNA methylation and accessibility dynamics at inflammation-associated regulatory TFs.

bioinformatics↗

bioRxiv2025

Dissecting regulatory syntax in human development with scalable multiomics and deep learning

Transcription factors (TFs) establish cell identity during development by binding regulatory DNA in a sequence-specific manner, often promoting local chromatin accessibility, and regulating gene expression. Mapping accessible chromatin offers critical insights into transcriptional control, but available datasets for human development are restricted to bulk tissue, single organs, or single modalities. Here, we present the Human Development Multiomic Atlas (HDMA), a single-cell atlas of chromatin accessibility and gene expression from 817,740 fetal cells across 12 organs, spanning 203 cell types and over 1 million candidate cis-regulatory elements, many of which exhibit organ-specific in vivo enhancer activity. Deep learning models trained to predict accessibility from local DNA sequence unravel a comprehensive lexicon of motifs which influence accessibility, including composite motifs exhibiting distinct syntactic constraints predicted to mediate TF cooperativity. We identify "hard" syntactic rules requiring precise motif spacing and orientation, "soft" rules allowing flexible motif arrangements, and ubiquitous motifs that inhibit accessibility. Model-based interpretation of genetic variants reveals that disruption of motifs with positive and negative effects is associated with concordant effects on gene expression. Our work delineates how motif syntax governs cell type-specific chromatin accessibility and provides a foundational resource for decoding cis-regulatory logic and interpreting genetic variation during human development.

genomics↗

bioRxiv2022

XIST ribonucleoproteins promote female sex-biased autoimmunity

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of numerous autoantigenic components, is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity. HIGHLIGHTSO_LITransgenic mouse models inducibly express Xist in male animals. C_LIO_LIXist expression in males induce autoantibodies and autoimmune pathology. C_LIO_LIXist in males reprograms T and B cell populations to female-like patterns. C_LIO_LIAutoantibodies to Xist RNP characterize female-biased autoimmune diseases. C_LI

molecular biology↗

bioRxiv2021

High Resolution Single Cell Maps Reveals Distinct Cell Organization and Function Across Different Regions of the Human Intestine

The colon is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota, and affects overall health. To better understand its organization, functions, and its regulation at a single cell level, we performed CODEX multiplexed imaging, as well as single nuclear RNA and open chromatin assays across eight different intestinal sites of four donors. Through systematic analyses we find cell compositions differ dramatically across regions of the intestine, demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighborhoods and communities highlighting distinct immunological niches present in the intestine. We also map gene regulatory differences in these cells suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation, and organization for this organ, and serve as an important reference map for understanding human biology and disease.

genomics↗

bioRxiv2021

Single-cell analyses reveal a continuum of cell state and composition changes in the malignant transformation of polyps to colorectal cancer

To chart cell composition and cell state changes that occur during the transformation of healthy colon to precancerous adenomas to colorectal cancer (CRC), we generated 451,886 single-cell chromatin accessibility profiles and 208,557 single-cell transcriptomes from 48 polyps, 27 normal tissues, and 6 CRCs collected from patients with and without germline APC mutations. A large fraction of polyp and CRC cells exhibit a stem-like phenotype, and we define a continuum of epigenetic and transcriptional changes occurring in these stem-like cells as they progress from normal to CRC. Advanced polyps contain increasing numbers of stem-like cells, regulatory T-cells, and a subtype of FOX-regulated pre-cancer associated fibroblasts. In the cancerous state, we observe T-cell exhaustion, RUNX1-regulated cancer associated fibroblasts, and increasing accessibility associated with HNF4A motifs in epithelia. Methylation changes in sporadic CRC are strongly anti-correlated with accessibility changes along this continuum, further identifying regulatory markers for molecular staging of polyps.

genomics↗