bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–08–10
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states.
  2. Unravelling cellular interactions using flow cytometry.
  3. Stromal senescence contributes to age-related increases in cancer.
  4. Is single-molecule protein sequencing here yet?
  5. Intestinal organoid models as tools to interrogate the physiology of human mucosal tissues and host-microbe interactions.
  6. Multi-modal clustering reveals event-free patient subgroup in colorectal cancer survival.
  7. Epiregulon: Single-cell transcription factor activity inference to predict drug response and drivers of cell states.
  8. Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.
  9. CellFuse Enables Multi-modal Integration of Single-cell and Spatial Proteomics data.
  10. Generative model for the first cell fate bifurcation in mammalian development.
  11. ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion.
  12. Younger Adults, Earlier Screening-What We Are Learning About Colorectal Cancer and What Comes Next.
  13. Capturing host-microbe interactions.
  1. Nat Genet. 2025 Aug 06.
    Comprehensive transcription factor perturbations recapitulate fibroblast transcriptional states.
    Kaden M Southard, Rico C Ardy, Anran Tang, Deirdre D O'Sullivan, Eli Metzner, Karthik Guruvayurappan, Thomas M Norman.
      Cell atlas projects have revealed that common cell types often comprise distinct, recurrent transcriptional states, but the function and regulation of these states remain poorly understood. Here, we show that systematic activation of transcription factors can recreate such states in vitro, providing tractable models for mechanistic and functional studies. Using a scalable CRISPR activation (CRISPRa) Perturb-seq platform, we activated 1,836 transcription factors in two cell types. CRISPRa induced gene expression within physiological ranges, with chromatin features predicting responsiveness. Comparisons with atlas datasets showed that transcription factor perturbations recapitulated key fibroblast states and identified their regulators, including KLF2 and KLF4 for a universal state present in many tissues, and PLAGL1 for a disease-associated inflammatory state. Inducing the universal state suppressed the inflammatory state, suggesting therapeutic potential. These findings position CRISPRa as a nuanced tool for perturbing differentiated cells and establish a general strategy for studying clinically relevant transcriptional states ex vivo.
    DOI:  https://doi.org/10.1038/s41588-025-02284-1
  2. Nat Methods. 2025 Aug 07.
    Unravelling cellular interactions using flow cytometry.
      
    DOI:  https://doi.org/10.1038/s41592-025-02743-x
  3. Nat Rev Cancer. 2025 Aug 04.
    Stromal senescence contributes to age-related increases in cancer.
    Jiayu Ye, Anupama Melam, Sheila A Stewart.
      Ageing is a process characterized by a wide array of cellular and systemic changes that together increase the risk of developing cancer. While cell-autonomous mutations within incipient tumour cells are important, age-related changes in the microenvironment are critical partners in the transformation process and response to therapy. However, aspects of ageing that are important and the degree to which they contribute to cancer remain obscure. One of the factors that impacts ageing is increased cellular senescence but it is important to note that ageing and cellular senescence are not synonymous. We highlight open questions, including if senescent cells have phenotypically distinct impacts in aged versus young tissue, or if it is the cell type that dictates the impact of senescence on tissue homeostasis and disease. Finally, it is probable that our current definition of cellular senescence encompasses more than one mechanistically distinct cellular state; thus, we highlight phenotypic differences that have been noted across cell types and tissues of origin. This Review focuses on the role that senescent stromal cells have in cancer, with a particular emphasis on fibroblasts given the amount of work that has focused on them.
    DOI:  https://doi.org/10.1038/s41568-025-00840-9
  4. Nat Methods. 2025 Aug;22(8): 1623-1628
    Is single-molecule protein sequencing here yet?
    Vivien Marx.
      
    DOI:  https://doi.org/10.1038/s41592-025-02767-3
  5. mSphere. 2025 Aug 07. e0082024
    Intestinal organoid models as tools to interrogate the physiology of human mucosal tissues and host-microbe interactions.
    J M Lemme-Dumit.
      The intestinal epithelium serves as a critical interface between the external environment and internal tissues, coordinating nutrient absorption, immune defense, and barrier integrity. Discerning the processes that maintain gut homeostasis has been challenging due to the complexity of the intestinal microenvironment and the difficulty in accessing human tissue. The advent of human intestinal organoid technology has transformed the field by providing relevant in vitro models that recapitulate the cellular diversity and function of the gut epithelium. A recent advance involves the integration of immune cells into organoid cultures, enabling the study of epithelial-immune cell interactions in both health and disease. Furthermore, the application of cutting-edge multi-omics approaches, including transcriptomics, proteomics, and metabolomics, has enabled a deeper understanding of intestinal cell signaling, niche factors, and host-microbe dynamics. These innovations have led to breakthroughs in translational research, particularly in the field of precision medicine. This minireview highlights how intestinal organoids derived from human tissue stem cells, coupled with high-resolution omics technologies, are advancing our knowledge of intestinal physiology, host responses, and disease mechanisms. It also describes the emergence of patient-derived organoids as tools to guide personalized therapeutic strategies for conditions such as inflammatory bowel disease and cystic fibrosis. As organoid models continue to evolve, the integration of additional tissue components-such as diverse immune cell lineages, stromal elements, vasculature, neural cells, and microbiota-will more accurately replicate the intricate nature of human physiology and broaden their translational potential.
    Keywords:  host response; human intestinal model; intestinal physiology; multi-omics; organoids; translational research
    DOI:  https://doi.org/10.1128/msphere.00820-24
  6. NPJ Syst Biol Appl. 2025 Aug 02. 11(1): 86
    Multi-modal clustering reveals event-free patient subgroup in colorectal cancer survival.
    Nikita Janakarajan, Guillaume Larghero, María Rodríguez Martínez.
      Colorectal cancer (CRC) benefits from a multi-omics-based stratification in the context of survival. Our TCGA-based study employs targeted feature selection and unsupervised clustering to stratify patients based on disease-specific survival, identifying an event-free subgroup undetectable with unimodal data or established consensus molecular subtypes. An analysis of variance and gene set enrichment coupled with clinical characterisation of the clusters reveal findings that support multi-omics-driven precision medicine in CRC.
    DOI:  https://doi.org/10.1038/s41540-025-00557-3
  7. Nat Commun. 2025 Aug 02. 16(1): 7118
    Epiregulon: Single-cell transcription factor activity inference to predict drug response and drivers of cell states.
    Tomasz Włodarczyk, Aaron Lun, Diana Wu, Minyi Shi, Xiaofen Ye, Shreya Menon, Shushan Toneyan, Kerstin Seidel, Liang Wang, Jenille Tan, Shang-Yang Chen, Timothy Keyes, Aleksander Chlebowski, Adrian Waddell, Wei Zhou, Yangmeng Wang, Qiuyue Yuan, Yu Guo, Liang-Fu Chen, Bence Daniel, Antonina Hafner, Meng He, Alejandro Chibly, Yuxin Liang, Zhana Duren, Ciara Metcalfe, Marc Hafner, Christian W Siebel, M Ryan Corces, Robert Yauch, Shiqi Xie, Xiaosai Yao.
      Transcription factors (TFs) and transcriptional coregulators are emerging therapeutic targets. Gene regulatory networks (GRNs) can evaluate pharmacological agents and identify drivers of disease, but methods that rely solely on gene expression often neglect post-transcriptional modulation of TFs. We present Epiregulon, a method that constructs GRNs from single-cell ATAC-seq and RNA-seq data for accurate prediction of TF activity. This is achieved by considering the co-occurrence of TF expression and chromatin accessibility at TF binding sites in each cell. ChIP-seq data allows motif-agonistic activity inference of transcriptional coregulators or TF harboring neomorphic mutations. Epiregulon accurately predicted the effects of AR inhibition across different drug modalities including an AR antagonist and an AR degrader, delineated the mechanisms of a SMARCA4 degrader by identifying context-dependent interaction partners, and prioritized drivers of lineage reprogramming and tumorigenesis. By mapping gene regulation across various cellular contexts, Epiregulon can accelerate the discovery of therapeutics targeting transcriptional regulators.
    DOI:  https://doi.org/10.1038/s41467-025-62252-5
  8. Genome Biol. 2025 Aug 06. 26(1): 233
    Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens.
    Lingling Wu, Xiang Zhu, Yanxia Liu, Dehua Zhao, Betty Chentzu Yu, Zheng Wei, Xueqiu Lin, Lei S Qi.
       BACKGROUND: Aging is a major risk factor for chronic diseases and cancer. Cellular aging, particularly in adult stem cells, offers a high-throughput framework for dissecting the molecular mechanisms of aging.
    RESULTS: We perform multiple genome-wide CRISPR interference (CRISPRi) screenings in human primary mesenchymal stem cells derived from adipose tissue during either replicative senescence or inflammation-induced senescence. These screens reveal distinct sets of potential novel regulators specific to each senescence pathway. Combining our perturbation-based functional genomic data with 405 genome-wide association study datasets, including 50 aging-related studies, we find that the inflammatory aging signatures identified from CRISPRi screenings are significantly associated with diverse aging processes, suggesting novel molecular signatures for analyzing and predicting aging status and aging-related disease.
    CONCLUSIONS: The signatures verified through comprehensive functional genomics and genetic analyses may provide new targets for modulating the aging process and enhancing the quality of cell therapy products.
    DOI:  https://doi.org/10.1186/s13059-025-03683-7
  9. bioRxiv. 2025 Jul 26. pii: 2025.07.23.665976. [Epub ahead of print]
    CellFuse Enables Multi-modal Integration of Single-cell and Spatial Proteomics data.
    Abhishek Koladiya, Zinaida Good, Sricharan Reddy Varra, Sean C Bendall, Kara L Davis.
      Single-cell and spatial proteomic technologies capture complementary biological information, yet no single platform can measure all modalities within the same cell. Most existing integration methods are optimized for transcriptomic data and rely on a large set of shared, strongly linked features, an assumption that often fails for low-dimensional proteomic modalities. We present CellFuse, a deep learning-based, modality-agnostic integration framework designed specifically for settings with limited feature overlap. CellFuse leverages supervised contrastive learning to learn a shared embedding space, enabling accurate cell type prediction and seamless integration across modalities and experimental conditions. Across a range of datasets including healthy PBMCs, bone marrow, CAR-T-treated lymphoma, and healthy and tumor tissues-CellFuse consistently outperforms existing methods in both integration quality and runtime efficiency. It maintains high accuracy even in the presence of missing markers and rare cell types, and performs robustly in cross-dataset comparisons, making it a powerful tool for scalable and high-fidelity single-cell data integration in basic and translational research.
    DOI:  https://doi.org/10.1101/2025.07.23.665976
  10. Development. 2025 Aug 05. pii: dev.204717. [Epub ahead of print]
    Generative model for the first cell fate bifurcation in mammalian development.
    Maria Avdeeva, Madeleine Chalifoux, Bradley Joyce, Stanislav Y Shvartsman, Eszter Posfai.
      The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in preimplantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, key transcription factors of TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.
    Keywords:  Bayesian modeling; First cell fate decision; Live imaging; Mouse; Preimplantation
    DOI:  https://doi.org/10.1242/dev.204717
  11. bioRxiv. 2025 Jul 21. pii: 2025.07.17.665404. [Epub ahead of print]
    ETS1 Orchestrates a Hybrid EMT Program Driving in vivo Metastasis and Immune Evasion.
    Benjamin Ziman, Talia A Wenger, Chehyun Nam, Qian Yang, Daniel Arnaudov, Megha Sheth, Zhixuan Jing, Yuhao Pan, Joe Vargas, Yong Teng, Uttam K Sinha, Young Min Park, De-Chen Lin.
      Transcriptional Intratumoral heterogeneity (ITH) is a hallmark of aggressive cancers, yet how transcriptional ITH programs drive tumor metastasis and immune evasion in upper aerodigestive squamous cell carcinoma (UASCC) remains unclear. Through single-cell RNA sequencing analysis of UASCC cells and patient tumors, we uncovered a hybrid epithelial mesenchymal transition (hEMT) ITH program linked to metastatic dissemination. The transcription factor ETS1 was identified as a master regulator of the hEMT program, directly activating pro-metastatic genes and promoting distant spread in vivo. Unexpectedly, ETS1 also orchestrated an immune-cold tumor microenvironment by transcriptionally activating both STAT1 and PD-L1 (CD274) genes, suppressing T lymphocyte infiltration, and elevating immune checkpoint molecules. Clinically, ETS1-high tumors strongly correlated with poor survival and resistance to immune checkpoint blockade across multiple cohorts. Leveraging drug screens, we discovered that ETS1-high cancers are vulnerable to HSP90 inhibitors (e.g., Alvespimycin), which suppress ETS1 by disrupting HIF1A-mediated transcriptional activation. Together, our work reveals ETS1 as a dual driver of tumor distal metastasis and immune evasion in UASCC, while nominating HSP90 inhibition as a tailored treatment strategy for ETS1-driven tumors. These findings provide a roadmap for targeting aggressive ITH subsets and overcoming immunotherapy resistance.
    DOI:  https://doi.org/10.1101/2025.07.17.665404
  12. JAMA. 2025 Aug 04.
    Younger Adults, Earlier Screening-What We Are Learning About Colorectal Cancer and What Comes Next.
    Caitlin C Murphy, Ami E Sedani, Bijal A Balasubramanian.
      
    DOI:  https://doi.org/10.1001/jama.2025.11473
  13. Nat Methods. 2025 Aug;22(8): 1620
    Capturing host-microbe interactions.
    Madhura Mukhopadhyay.
      
    DOI:  https://doi.org/10.1038/s41592-025-02787-z
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