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Zheng, E.

Publications and source records attributed to Zheng, E..

10 recordsLinked to original sources
bioRxiv2026

Chemotherapy-induced multicellularity drives drug-tolerant persistence state in tumor cells

Multicellularity is a well-documented microbial response to stress, however its role as an adaptive survival strategy in cancer remains unresolved. Here we reveal that drug stress, such as paclitaxel treatment, enable rapidly (within 24-48 hours) and efficiently ([~]20-40%) convert single mouse breast 4T1 cancer cells into clonal multicellular spheroids, ultimately generating multicellular masses. Notably, multicellularity is reversible: upon stress removal, most of them restore a unicellular lifestyle that quickly becomes dominant. This transient multicellular state shields cells from hostile niches, functions as a drug-tolerant persistence (DTP) reservoir, and fuels post-therapy relapse, revealing multicellularity as a facultative evolutionary pivot for fitness gain. Importantly, blocking primordial germ cell (PGC) specification suppresses the multicellularity transition. Our findings reveal that certain cancer cells enable adopt unicellular-multicellular life cycle through phenotypic plasticity, dynamically adapting to microenvironmental shifts to maximize fitness. This discovery reframes cancer evolution and the drug-tolerant persistence (DTP) state, highlighting multicellularity as an adaptive, stress-inducible survival strategy against therapy. HighlightO_LIDrug induced evolution from unicell to clonal multicellularity. C_LIO_LIProviding a novel DTP state. C_LIO_LIRevealing environment-dependent bistable plasticity: multicellular persistence (stress) versus unicellular proliferation (favorable). C_LIO_LIBlocking primordial germ cell (PGC) specification suppresses the multicellularity. C_LI

cancer biology↗
bioRxiv2026

Adaptive plasticity of aspartate metabolism in succinate dehydrogenase-deficient cancer cells

Succinate dehydrogenase (SDH) supports cancer cell proliferation by enabling oxidative biosynthesis of the amino acid aspartate, yet SDH loss can also drive tumorigenesis. To cope with SDH loss, cancer cells can engage alternative aspartate synthesis pathways; however, the variables dictating pathway usage and adaptive mechanisms involved are incompletely understood. Here, we systematically profile the adaptation of SDH-knockout cancer cells and find that cells can adapt to SDH loss via at least two distinct mechanisms: suppression of respiratory complex I or upregulation of pyruvate carboxylase. Each route gives rise to distinct metabolic states with both shared and unique dependencies, but either route allows cells to overcome aspartate limitation, improve proliferative fitness, and mitigate pyrimidine-dependent replication stress. Overall, this work provides a comprehensive view of adaptive aspartate synthesis in SDH-deficient cancer cells, highlights a remarkable redox-constrained metabolic plasticity, and nominates potential metabolic vulnerabilities likely to be shared among SDH-deficient cancer cells.

cancer biology↗
bioRxiv2026

The Common Fund Data Ecosystem (CFDE)

The NIH Common Fund Data Ecosystem (CFDE) integrates data resources from 18 NIH Common Fund programs for discovery and integrative analysis. These programs generate valuable but heterogeneous datasets that can be difficult to discover, access, and reuse. CFDE aims to provide a collaborative, community-built infrastructure that links and enriches Common Fund programs. We describe the evolution, structure, and core technologies of CFDE, including practical approaches that support submission, integration, visualization, and public release of multimodal data. Training programs and workforce initiatives lower barriers to adoption. CFDE has devised solutions to critical issues facing cross-program initiatives, including data scale and heterogeneity, dataset integration, and long-term sustainability. We demonstrate the utility of linking Common Fund resources through integrative tools and cross-dataset queries to yield insights that would otherwise be infeasible. Collectively, CFDE shows that a standards-driven, federated approach enhances and unifies cross-disciplinary resources, fostering collaboration and data-driven discovery.

scientific communication and education↗
bioRxiv2026

Exploiting HLA-II Promiscuity via Peptide Terminal Overhang Recognition for Pan-Allelic and Tumor-Selective AML Immunotherapy

Antibodies targeting peptides presented by human leukocyte antigen (HLA) molecules expand the therapeutic landscape by enabling recognition of intracellular antigens. While most efforts have focused on allele-restricted peptides presented by HLA class I (HLA-I), HLA class II (HLA-II) epitopes remain underexplored despite their potential for promiscuous presentation. Acute myeloid leukemia (AML) is characterized by high expression of both HLA-II and the myeloid lineage antigen myeloperoxidase (MPO). Here, we identified an MPO-derived epitope (MPO100-132) that is promiscuously presented by multiple HLA-II molecules. We generated a MPO100-132-specific antibody (146D5) that recognizes the N-terminal overhang of this peptide independent of specific HLA contacts, enabling pan-allelic recognition. Engineered into bispecific T cell engagers (BiTEs), this antibody mediated robust cytotoxicity against primary AML samples across diverse HLA-II backgrounds. Crucially, 146D5-based BiTEs selectively spared normal myeloid cells, indicating that the MPO100-132 peptide, derived from the MPO propeptide, was functionally undetectable in normal myeloid cells, providing a significant safety window. In vivo, the MPO-targeting BiTE demonstrated potent antitumor activity and prolonged survival in AML xenograft models. Our findings identify peptide terminal overhangs as an actionable class of antibody targets and introduce a strategy to exploit HLA-II promiscuity for broadly applicable HLA-dependent but allele-agnostic immunotherapies.

immunology↗
bioRxiv2025

Rewiring of 3D chromatin topology orchestrates transcriptional reprogramming in muscle fiber-type specification and transformation

The composition of muscle fibers, characterized by distinct contractile and metabolic properties, significantly influences meat quality and glucose homeostasis. However, the mechanisms by which three-dimensional (3D) genome topology integrates with epigenetic states to regulate muscle fiber specification and transformation remain poorly understood. Here, we present an integrative analysis of the transcriptome, epigenome, and 3D genome architecture in the slow-twitch glycolytic extensor digitorum longus (EDL) and fast-twitch oxidative soleus (SOL) muscles. Global remodeling of enhancer-promoter (E-P) interactions emerged as a central driver of transcriptional reprogramming associated with muscle contraction and glucose metabolism. We identified tissue-specific super-enhancers (SEs) that regulate muscle fiber-type specification through cooperation of chromatin looping and transcription factors such as KLF5. Notably, the SE-driven activation of STARD7 facilitated the transformation of glycolytic fibers into oxidative fibers by mitigating reactive oxygen species levels and suppressing ERK MAPK signaling. This study elucidates the principles of 3D genome organization in the epigenetic regulation of muscle fiber specification and transformation, providing a foundation for novel therapeutic strategies targeting metabolic disorders and enhancing meat quality. O_FIG O_LINKSMALLFIG WIDTH=142 HEIGHT=200 SRC="FIGDIR/small/643571v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@990eecorg.highwire.dtl.DTLVardef@a2b491org.highwire.dtl.DTLVardef@1fcd142org.highwire.dtl.DTLVardef@10e4d47_HPS_FORMAT_FIGEXP M_FIG Schematic overview of the study. C_FIG

developmental biology↗
bioRxiv2025

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis

Decreased availability of the amino acid aspartate can constrain cell function in diverse biological contexts, but the temporal interplay between aspartate, downstream metabolic changes, and functional effects remains poorly understood. Using an aspartate biosensor and live-cell imaging, we examine the interaction between aspartate abundance and cell proliferation in several models of aspartate limitation. While aspartate deficiencies intuitively interface with proliferation in some contexts, aspartate limitation from succinate dehydrogenase (SDH) inhibition causes strikingly nonintuitive dynamics resulting from an outsized impairment of pyrimidine synthesis. Mechanistically, we find that SDH loss impairs pyrimidine biosynthesis by decreasing aspartate and accumulating succinate, which competitively inhibits mammalian aspartate transcarbamylase (ATCase). This metabolic interaction persists in multiple models of SDH deficiency, causing pyrimidine insufficiency, replication stress, and sensitivity to ATR kinase inhibition. These findings define a novel role for succinate in modulating cellular nucleotide homeostasis, suggest a potential therapeutic vulnerability of SDH-deficient tumors, and demonstrate how cascading metabolic interactions can unfold to impact cell function.

cell biology↗
bioRxiv2024

Multi-omic characterization of allele-specific regulatory variation in hybrid pigs

Genetic variation in the regulation of gene expression contributes substantially to phenotypic variation. Understanding how variation in DNA sequences and epigentic modifications leads to gene expression variation remains a challenging task. In hybrid animals where cellular environments are homogeneous, differences between the expression of paternal and maternal alleles must be due to cis sequence or epigenic differences. Therefore, hybrid mapping is a powerful approach to efficiently identify and characterize genes under regulation through mechanisms in cis. In this study, using reciprocal crosses of the phenotypically divergent Duroc and Lulai pig breeds, we performed a comprehensive multi-omic characterization of regulatory variation across brain, liver, muscle, and placenta in four developmental stages. We produced one of the largest multi-omic datasets to date in pigs, including 16 whole genome sequenced genomes, 48 whole genome bisulfite sequencing, 168 ATAC-Seq and 168 RNA-Seq samples. We developed a novel read count-based method to reliably assess allele-specific methylation, chromatin accessibility, and RNA expression. We showed that tissue specificity was much stronger than developmental stage specificity in all of DNA methylation, chromatin accessibility, and gene expression. We identified 573 genes showing allele specific expression, including those influenced by parent-of-origin as well as allele genotype effects. By integrating methylation, chromatin accessibility, and gene expression data, many of these allele specific expression can be explained by allele specific methylation and/or chromatin accessibility. This study provides one of the most comprehensive characterizations of regulatory variation across multiple tissues and developmental stages in pigs and offers new opportunity of genetic improvement for this important food animal species.

developmental biology↗
bioRxiv2022

Nucleotide resolution genetic mapping in pigs by publicly accessible whole genome imputation

Genetic mapping to identify genes and alleles associated with or causing economically important quantitative trait variation in livestock animals such as pigs is a major goal in the genetic improvement animals. Despite recent advances in high throughput genotyping technologies, resolution of genetic mapping in pigs remains poor due in part to the low density of genotyped variant sites. In this study, we overcame this limitation by developing a reference haplotype panel for pigs based on 2,259 whole genome sequenced animals representing 44 pig breeds. We optimized the imputation procedure to achieve an average concordance rate in excess of 97%, non-reference concordance rate 91%, and r2 0.89. We demonstrated that genotype imputation using this resource can dramatically improve resolution of genetic mapping. Finally, we developed a public web server (swimgeno.org) to allow the pig genetics community to fully utilize this resource. We expect the resource and server to significantly facilitate genetic mapping and accelerate genetic improvement in pigs.

genomics↗
bioRxiv2018

Generation of a novel growth-enhanced and reduced environmental impact transgenic pig strain

In pig production, insufficient feed digestion causes excessive nutrients such as phosphorus and nitrogen, which are then released to the environment. To address the issue of environmental emissions, we have established transgenic pigs harboring a single-copy quad-cistronic transgene and simultaneously expressing three microbial enzymes, {beta}-glucanase, xylanase, and phytase in the salivary glands. All the transgenic enzymes were successfully expressed, and the digestion of non-starch polysaccharides (NSPs) and phytate in the feedstuff was enhanced. Fecal nitrogen and phosphate outputs were reduced by 23%-46%, and growth rate improved by 23.4% (gilts) and 24.4% (boars) when the pigs were fed on a corn and soybean-based diet and high-NSP diet. The transgenic pigs showed a 11.5%- 14.5% improvement in feed conversion rate compared to the age-matched wild-type littermates. These findings indicate that transgenic pigs are promising resources for improving feed efficiency and reducing nutrient emissions to the environment.

biochemistry↗