Zihan Xu

All Publications

• Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features. Nature communications Xu, Z., Ugurbil, A., Kwan, J., Schaefer, C., Abdulraouf, A., Lu, Z., Tang, E., Zhou, W., Cao, J. 2026; 17 (1)

  Abstract

  Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.

  View details for DOI 10.1038/s41467-026-75360-7

  View details for PubMedID 42493507

  View details for PubMedCentralID PMC13396447

• Mapping convergent regulators of melanoma drug resistance by PerturbFate. Nature Xu, Z., Lu, Z., Ugurbil, A., Abdulraouf, A., Liao, A., Zhang, J., Zhou, W., Cao, J. 2026; 654 (8117): 261-271

  Abstract

  High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.

  View details for DOI 10.1038/s41586-026-10367-0

  View details for PubMedID 41986722

  View details for PubMedCentralID PMC13233327

• Dissecting key regulators of transcriptome kinetics through scalable single-cell RNA profiling of pooled CRISPR screens. Nature biotechnology Xu, Z., Sziraki, A., Lee, J., Zhou, W., Cao, J. 2024; 42 (8): 1218-1223

  Abstract

  We present a combinatorial indexing method, PerturbSci-Kinetics, for capturing whole transcriptomes, nascent transcriptomes and single guide RNA (sgRNA) identities across hundreds of genetic perturbations at the single-cell level. Profiling a pooled CRISPR screen targeting various biological processes, we show the gene expression regulation during RNA synthesis, processing and degradation, miRNA biogenesis and mitochondrial mRNA processing, systematically decoding the genome-wide regulatory network that underlies RNA temporal dynamics at scale.

  View details for DOI 10.1038/s41587-023-01948-9

  View details for PubMedID 37749268

  View details for PubMedCentralID PMC10961254

• Optics-free spatial genomics for mapping mammalian brain aging by IRISeq. Nature neuroscience Abdulraouf, A., Jiang, W., Zhang, Z., Xu, Z., Lu, Z., Merlinsky, T., Liao, A., Doymaz, A., Isakov, S., Raihan, T., Zhou, W., Cao, J. 2026; 29 (7): 1762-1773

  Abstract

  Spatial transcriptomics has emerged as a transformative approach for in situ mapping of cellular heterogeneity and interactions, yet existing methods often compromise throughput, cost and tissue coverage. Here we introduce Imaging Reconstruction using Indexed Sequencing (IRISeq): an optics-free, cost-effective platform that leverages spatial interaction mapping by indexed sequencing to profile tissues at adjustable sizes and resolutions (5-50 µm). We applied IRISeq to map gene expression across more than 70 coronal sections from both adult and aged mouse brains, including wild-type and two lymphocyte-deficient models (Rag1 and Prkdc mutants) and generated more than 460,000 spatial transcriptome profiles. Our integrated analysis with 783,264 single-cell transcriptomes revealed region-specific aging signatures that are lymphocyte dependent, notably a downregulation of interferon signaling and inflammation in ventricular regions upon lymphocyte depletion, alongside mutant-specific upregulation of senescence pathways. Furthermore, lymphocyte deficiency was linked to preserved abundance of ependymal cells that line the brain's ventricles and to distinct microglial state dynamics, highlighting a key role for lymphocytes in driving inflammatory processes during brain aging. Overall, IRISeq provides a high-throughput and cost-effective solution for spatially resolved transcriptomic profiling, opening new avenues for elucidating region-specific cellular mechanisms underlying aging and identifying potential therapeutic targets to preserve brain homeostasis.

  View details for DOI 10.1038/s41593-026-02293-1

  View details for PubMedID 42120609

  View details for PubMedCentralID PMC13337494

• Transcript-guided targeted cell enrichment for scalable single-nucleus RNA sequencing. Cell genomics Liao, A., Zhang, Z., Sziraki, A., Abdulraouf, A., Rehman, A., Xu, Z., Lu, Z., Jiang, W., Arya, A., Lee, J., Maragkakis, M., Zhou, W., Cao, J. 2026; 6 (3): 101101

  Abstract

  Large-scale single-cell atlases have revealed many aging- and disease-associated cell types, yet these populations are often underrepresented in heterogeneous tissues, limiting detailed molecular analyses. To address this, we developed EnrichSci-a scalable, microfluidics-free platform that combines hybridization chain reaction RNA fluorescence in situ hybridization (FISH) with combinatorial indexing to profile single-nucleus transcriptomes of target cell types with full gene-body coverage. Applied to oligodendrocytes in the aging mouse brain, EnrichSci uncovered aging-associated molecular dynamics across distinct oligodendrocyte subtypes, revealing both shared and subtype-specific gene expression changes. Additionally, we identified aging-associated exon-level signatures missed by conventional gene-level analyses, highlighting post-transcriptional regulation as a critical dimension of cell-state dynamics in aging. By coupling transcript-guided enrichment with a scalable sequencing workflow, EnrichSci provides a versatile approach to decode dynamic regulatory landscapes in diverse cell types from complex tissues.

  View details for DOI 10.1016/j.xgen.2025.101101

  View details for PubMedID 41386229

  View details for PubMedCentralID PMC12985360

• Organism-wide cellular dynamics and epigenomic remodeling in mammalian aging. Science (New York, N.Y.) Lu, Z., Zhang, Z., Xu, Z., Abdulraouf, A., Zhou, W., Cao, J. 2026; 391 (6788): eadw6273

  Abstract

  To investigate organism-wide cellular alterations and epigenomic dynamics during aging, we constructed a single-cell chromatin accessibility atlas spanning 21 mouse tissues across three age groups and both sexes. We found that around one-quarter of 536 organ-specific cell types and 1828 finer-grained subtypes exhibited considerable age-related population shifts. Cellular states from broadly distributed lineages displayed synchronized dynamics with age, indicating systemic signals that coordinate these changes. Molecular analyses identified both intrinsic regulators (chromatin peaks, transcription factor activity) and extrinsic factors (cytokine programs) underlying these shifts. Moreover, ~40% of aging-associated population dynamics were sex-dependent, with tens of thousands of peaks altered exclusively in one sex. Together, these findings present a comprehensive framework for how aging reshapes the chromatin landscape and cellular composition across diverse tissues.

  View details for DOI 10.1126/science.adw6273

  View details for PubMedID 41747035

• Perturb-ME: Scalable mechanism discovery from phenotype-enriched genome-wide screens BioRxiv Wang, H., Gu, J., Frangieh, C., Cuoco, M., Zhao, M., Sett, A., Beyer, T., Pang, K., Stolte, E., Xu, Z., Leskovec, J., Rozenblatt-Rosen, O., Natarajan, V., Geiger-Schuller, K., Thakore, P., Regev, A. 2026

  View details for DOI 10.64898/2026.08.17.745330

• A global view of aging and Alzheimer's pathogenesis-associated cell population dynamics and molecular signatures in human and mouse brains. Nature genetics Sziraki, A., Lu, Z., Lee, J., Banyai, G., Anderson, S., Abdulraouf, A., Metzner, E., Liao, A., Banfelder, J., Epstein, A., Schaefer, C., Xu, Z., Zhang, Z., Gan, L., Nelson, P. T., Zhou, W., Cao, J. 2023; 55 (12): 2104-2116

  Abstract

  Conventional methods fall short in unraveling the dynamics of rare cell types related to aging and diseases. Here we introduce EasySci, an advanced single-cell combinatorial indexing strategy for exploring age-dependent cellular dynamics in the mammalian brain. Profiling approximately 1.5 million single-cell transcriptomes and 400,000 chromatin accessibility profiles across diverse mouse brains, we identified over 300 cell subtypes, uncovering their molecular characteristics and spatial locations. This comprehensive view elucidates rare cell types expanded or depleted upon aging. We also investigated cell-type-specific responses to genetic alterations linked to Alzheimer's disease, identifying associated rare cell types. Additionally, by profiling 118,240 human brain single-cell transcriptomes, we discerned cell- and region-specific transcriptomic changes tied to Alzheimer's pathogenesis. In conclusion, this research offers a valuable resource for probing cell-type-specific dynamics in both normal and pathological aging.

  View details for DOI 10.1038/s41588-023-01572-y

  View details for PubMedID 38036784

  View details for PubMedCentralID PMC10703679

• Tracking cell-type-specific temporal dynamics in human and mouse brains. Cell Lu, Z., Zhang, M., Lee, J., Sziraki, A., Anderson, S., Zhang, Z., Xu, Z., Jiang, W., Ge, S., Nelson, P. T., Zhou, W., Cao, J. 2023; 186 (20): 4345-4364.e24

  Abstract

  Progenitor cells are critical in preserving organismal homeostasis, yet their diversity and dynamics in the aged brain remain underexplored. We introduced TrackerSci, a single-cell genomic method that combines newborn cell labeling and combinatorial indexing to characterize the transcriptome and chromatin landscape of proliferating progenitor cells in vivo. Using TrackerSci, we investigated the dynamics of newborn cells in mouse brains across various ages and in a mouse model of Alzheimer's disease. Our dataset revealed diverse progenitor cell types in the brain and their epigenetic signatures. We further quantified aging-associated shifts in cell-type-specific proliferation and differentiation and deciphered the associated molecular programs. Extending our study to the progenitor cells in the aged human brain, we identified conserved genetic signatures across species and pinpointed region-specific cellular dynamics, such as the reduced oligodendrogenesis in the cerebellum. We anticipate that TrackerSci will be broadly applicable to unveil cell-type-specific temporal dynamics in diverse systems.

  View details for DOI 10.1016/j.cell.2023.08.042

  View details for PubMedID 37774676

  View details for PubMedCentralID PMC10545416

• Induced lineage promiscuity undermines the efficiency of all-trans-retinoid-acid-induced differentiation of acute myeloid leukemia ISCIENCE Tang, Y., Tian, X., Xu, Z., Cai, J., Liu, H., Liu, N., Chen, Z., Chen, S., Liu, F. 2021; 24 (5)

  View details for DOI 10.1016/j.isci.2021.102410

  View details for Web of Science ID 000653990500025