bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–07–19
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Spatio-DARLIN maps cell state and clonal history in intact mouse tissues.
  2. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  3. Single cell multiomics unravel the transcription networks controlling the different EMT tumor states.
  4. An encyclopedia of human enhancer-gene regulatory interactions.
  5. Transcription factor targeting strategies in cancer: mechanisms, challenges and cutting-edge progress.
  6. Regenerative Inflammation in IBD: How Type I Interferons and TNF Cross-Talk Converts Epithelial Repair into Therapeutic Response.
  7. DNA-shredding CRISPR enzyme takes aim at cancer cells.
  8. CRISPR gets a power boost from AI-designed 'molecular scissors'.
  9. Robust regulatory interplay of enhancers, facilitators, and promoters in a native chromatin context.
  10. Translational cell fate reprogramming and regenerative medicine enabled by microphysiological systems.
  11. Epithelial regeneration in the gastrointestinal tract.
  12. Programmable regenerative tissues: Converging mammalian synthetic biology and tissue engineering.
  13. Bispecific antibodies.
  1. Nat Methods. 2026 Jul 17.
    Spatio-DARLIN maps cell state and clonal history in intact mouse tissues.
      
    DOI:  https://doi.org/10.1038/s41592-026-03157-z
  2. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  3. Nat Commun. 2026 Jul 11.
    Single cell multiomics unravel the transcription networks controlling the different EMT tumor states.
    Andrea Pérez-González, Gabriel Windels, Kevin Bévant, Justine Lengrand, Sophie Lemaire, Virginie Moers, Samuel Scozzaro, Ulysse Debroux, Christine Dubois, Sebastiaan Vanuytven, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) is a dynamic process during which cells lose their epithelial characteristics and acquire mesenchymal traits. In cancer, EMT is closely associated with tumor initiation, progression, invasion, metastasis, and therapy resistance. Rather than being a binary state switch, EMT encompasses a spectrum of tumor states with distinct functional properties. However, the transcription factors (TFs) that govern transitions between these EMT states remain poorly defined. Here, using multi-omic approaches combining single-cell RNA-seq and single-cell ATAC-seq, we delineate the transcriptomic and chromatin landscapes of distinct EMT states in a mouse model of skin squamous cell carcinoma (SCC). Through CRISPR/Cas9-mediated loss-of-function studies coupled with in vitro and in vivo functional assays, we identify TFs regulating specific EMT states. Klf5 and Pitx1 control the early stages of EMT and are essential for metastasis formation. In contrast, Nfatc1 and Creb3l1 act at later stages of EMT. Similar EMT states and regulatory patterns are found in mouse pancreatic adenocarcinoma and human cancers. Altogether, our study defines the transcriptional and chromatin landscape controlling EMT progression in mouse skin SCC, identifies EMT state-specific TFs and highlights their essential roles in regulating metastasis.
    DOI:  https://doi.org/10.1038/s41467-026-75521-8
  4. Nature. 2026 Jul 15.
    An encyclopedia of human enhancer-gene regulatory interactions.
    Andreas R Gschwind, Kristy S Mualim, Alireza Karbalayghareh, Maya U Sheth, Kushal K Dey, Evelyn Jagoda, Ramil N Nurtdinov, Wang Xi, Anthony S Tan, James Galante, Hank Jones, X Rosa Ma, David Yao, Dulguun Amgalan, Judhajeet Ray, Chad J Munger, Joseph Nasser, Žiga Avsec, Benjamin T James, Muhammad S Shamim, Neva C Durand, Suhas S P Rao, Ragini Mahajan, Benjamin R Doughty, Kalina Andreeva, Jacob C Ulirsch, Kaili Fan, Elizabeth M Perez, Tri C Nguyen, David R Kelley, Hilary K Finucane, Jill E Moore, Zhiping Weng, Manolis Kellis, Michael C Bassik, Berk Ustun, Alkes L Price, Michael A Beer, Roderic Guigó, John A Stamatoyannopoulos, Erez Lieberman Aiden, William J Greenleaf, Christina S Leslie, Lars M Steinmetz, Anshul Kundaje, Jesse M Engreitz.
      Identifying transcriptional enhancers and their target genes is essential for understanding gene regulation and the effect of human genetic variation on disease1-6. Here we create and evaluate a resource of more than 92 million enhancer-gene regulatory interactions across 1,458 biosamples covering 369 cell types and tissues, by integrating predictive models, chromatin states, three-dimensional contacts and large-scale genetic perturbations generated by the ENCODE Consortium7. We first create a systematic benchmarking pipeline to compare predictive models, assembling a dataset of 10,356 element-gene pairs measured in CRISPR perturbation experiments, more than 30,000 fine-mapped expression quantitative trait loci and 569 fine-mapped genome-wide association study (GWAS) variants linked to a probable causal gene. Using this framework, we develop ENCODE-rE2G, a predictive model achieving state-of-the-art performance across several prediction tasks, demonstrating that iterative perturbations and supervised machine learning can build increasingly accurate predictive models of enhancer regulation. Using ENCODE-rE2G, we build an encyclopedia of enhancer-gene regulatory interactions in the human genome, revealing global properties of enhancer networks, identifying differences in regulatory complexity across genes and improving analyses linking noncoding variants to target genes and cell types for common complex diseases. By interpreting the model, we find that beyond enhancer activity and three-dimensional enhancer-promoter contacts, additional features that guide enhancer-promoter communication include promoter class and enhancer-enhancer synergy. These genome-wide maps of enhancer-gene regulatory interactions, benchmarking software, predictive models and insights about enhancer function provide a valuable resource for future studies of gene regulation and human genetics.
    DOI:  https://doi.org/10.1038/s41586-026-10781-4
  5. Acta Pharmacol Sin. 2026 Jul 14.
    Transcription factor targeting strategies in cancer: mechanisms, challenges and cutting-edge progress.
    Hui Chen, Rong Fu, Zhao-Qiu Wu.
      Transcription factors (TFs) occupy a central position in cancer biology, functioning as master regulators that translate genetic, epigenetic and environmental cues into cell fate decisions, proliferation, survival, and therapy response. Historically deemed "undruggable" owing to their lack of catalytic sites, conformational flexibility, and engagement in broad protein-DNA and protein-protein interfaces, TFs were long considered beyond the reach of conventional pharmacology. Over the past decades, advances in structural biology, chemical biology, epigenetics, and nucleic acid therapeutics have begun to overcome these challenges, revealing actionable vulnerabilities within TF networks. This review synthesizes current understanding of TF function in tumorigenesis, moving from mechanistic insights at the level of individual TFs to the higher-order organization of transcriptional regulatory networks. It further assesses emerging therapeutic strategies aimed at perturbing aberrant TF activity, encompassing direct inhibition, targeted protein degradation, modulation of TF-cofactor interactions, and nucleic acid-based interventions. We further highlight exemplary TFs and their typical targeting strategies, including Myelocytomatosis oncogene (MYC), Signal transducer and activator of transcription 3 (STAT3), Catenin beta-1 (β-catenin), Yes-associated protein/Transcriptional coactivator with PDZ-binding motif/Transcriptional enhanced associate domain (YAP/TAZ/TEAD), Estrogen receptor/Androgen receptor (ER/AR), and Phosphatase and tensin homolog/Protein kinase B/Forkhead box O (PTEN/AKT/FOXO), which illustrating mechanistic understanding of transcriptional regulation drives therapeutic development and enables genomics-guided precision oncology. By unifying mechanistic insight with pharmacological innovation, we aim to provide a conceptual framework for targeting the transcriptional architecture of cancer and charting paths toward next-generation transcription-directed therapies.
    Keywords:  cancer therapy; drugging the undruggable; epigenetic regulation; precision oncology; transcription factors; transcriptional regulation
    DOI:  https://doi.org/10.1038/s41401-026-01877-8
  6. Cells. 2026 Jun 24. pii: 1144. [Epub ahead of print]15(13):
    Regenerative Inflammation in IBD: How Type I Interferons and TNF Cross-Talk Converts Epithelial Repair into Therapeutic Response.
    Emelia A M Hinton, Roslyn A Kemp, Michael Schultz, Safina Gadeock.
      Inflammatory bowel diseases (IBD) are increasingly recognized as disorders in which epithelial dysfunction and maladaptive regeneration may be as important as immune dysregulation. Tumor necrosis factor (TNF), a key mediator of intestinal inflammation and a therapeutic target, plays a dual role in both immune activation and epithelial repair by regulating progenitor cell expansion, lineage plasticity, and chemokine signaling in the intestinal epithelium. During acute injury, TNF-associated responses are generally considered adaptive, supporting crypt repair, barrier restitution, and secretory remodeling pathways. However, in chronic disease, persistent TNF exposure, potentially reinforced by type I interferons (IFN-I), may contribute to the persistence of epithelial regenerative pathways. IFN-I signaling has been suggested in experimental and translational studies to reinforce chemokine networks and transcriptional imprinting. We propose that this potentially converts physiological repair into a sustained state of what we have termed "regenerative inflammation," in which epithelial-derived signals may perpetuate immune recruitment and tissue remodeling. Such TNF-IFN-imprinted epithelial states may contribute to sustained pathology in a subset of patients and could be associated with reduced responsiveness to anti-TNF therapy, although direct causal evidence in human disease remains limited. By integrating mechanistic, organoid-based, and clinical observational evidence, we propose that chronic TNF-IFN crosstalk may contribute to a self-sustaining regenerative inflammatory circuit, providing a conceptual framework for disease persistence in IBD and highlighting potential opportunities to target epithelial-immune interactions.
    Keywords:  TNF; epithelial memory; epithelial regeneration; inflammatory bowel disease; organoids; regenerative inflammation; therapeutic resistance; type I interferons
    DOI:  https://doi.org/10.3390/cells15131144
  7. Nature. 2026 Jul 14.
    DNA-shredding CRISPR enzyme takes aim at cancer cells.
    Mehran Takallo, Raymond H J Staals.
      
    Keywords:  Biochemistry; Biotechnology; Medical research; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-02122-2
  8. Nature. 2026 Jul 16.
    CRISPR gets a power boost from AI-designed 'molecular scissors'.
    Amanda Heidt.
      
    Keywords:  CRISPR-Cas9 genome editing; Machine learning; Molecular biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-026-02217-w
  9. Cell. 2026 Jul 17. pii: S0092-8674(26)00753-1. [Epub ahead of print]
    Robust regulatory interplay of enhancers, facilitators, and promoters in a native chromatin context.
    Zhou Zhou, Yang Cheng, Jaret Lieberth, Junke Zhang, Yiyang Jin, Albert Li, Haiyuan Yu, Abdullah Ozer, John T Lis.
      Enhancers are abundant and critical gene-distal cis-regulatory elements with distinct architectural features; however, a mechanistic understanding of their interactions within endogenous chromatin contexts remains challenging. Here, we developed a recombinase-mediated genome-rewriting platform to explore how a long-range human enhancer, eNMU, confers a remarkable 10,000-fold activation of its target gene, Neuromedin U (NMU), at its native locus. Our systematic dissection reveals two functionally distinct sub-elements of eNMU: the canonical autonomous enhancer e1 and the intrinsically inactive facilitator e2, which dramatically augments e1's activity. The autonomous enhancer e1 is functionally hierarchical to e2, additional facilitators, and the NMU promoter across the ∼100-kb NMU-eNMU region, and it orchestrates the formation of a 3D regulatory hub. e1 also harbors a bipartite structure: a divergently transcribed retroviral long terminal repeat (LTR) enhancer and an adjacent LTR promoter that dampens NMU expression. We explore and discuss the broader implications of our focused study for understanding enhancer regulatory mechanisms genome-wide.
    Keywords:  GATA1; LTR; NMU; RUNX1; STAT5; enhancers; facilitators; promoters; transcription factors; transcription regulation
    DOI:  https://doi.org/10.1016/j.cell.2026.06.033
  10. Curr Opin Genet Dev. 2026 Jul 11. pii: S0959-437X(26)00079-1. [Epub ahead of print]100 102512
    Translational cell fate reprogramming and regenerative medicine enabled by microphysiological systems.
    Hrithiha Sriramulu, Hyunsung Woo, Anavi Kaul, Samira Musah.
      Recent advances in genetic engineering and in vivo reprogramming have opened transformative possibilities for controlling cell fate in tissue repair and regeneration. However, clinical translation remains constrained by the limited predictive value of animal models and traditional in vitro systems, which often fail to fully recapitulate human responses, including the physiological consequences of genetic manipulations. Emerging microphysiological systems, exemplified by three-dimensional organoids and organs-on-chips (OoCs) systems, help bridge this gap by recreating key aspects of human physiology while enabling precise bioengineering of the niche to modulate cell fate decisions and plasticity. Organoids derived from induced pluripotent stem cells, adult stem cells, primary tissues, or directly reprogrammed cells preserve the patient-specific genetic background, facilitating mechanistic studies of development and disease and the evaluation of gene correction and reprogramming strategies in a human-relevant context. Complementarily, OoC platforms provide regulated perfusion, tissue vascularization, mechanical forces, molecular gradients, and immune cell integration to promote tissue maturation, functional readouts, and quantitative assessment of therapeutic responses that are difficult to achieve in static cultures. In this review, we discuss how organoids and OoC-based platforms are being leveraged to study and enhance cell fate reprogramming, repair, and regeneration across multiple tissues. We highlight recent reports where these systems informed the design, optimization, and safety evaluation of gene and cell therapies. Finally, we outline current limitations, including scalability, standardization, and biomaterial constraints, and propose future directions for integrating organoids, OoC, and gene-modulation technologies to enable more predictive, personalized, and clinically translatable regenerative medicine.
    DOI:  https://doi.org/10.1016/j.gde.2026.102512
  11. Curr Opin Genet Dev. 2026 Jul 15. pii: S0959-437X(26)00082-1. [Epub ahead of print]100 102515
    Epithelial regeneration in the gastrointestinal tract.
    Eunah Kim, Bon-Kyoung Koo.
      The gastrointestinal tract possesses a remarkable regenerative capacity to maintain tissue homeostasis against various injuries. However, the intestine and stomach exhibit distinct regenerative strategies. In the intestine, damage to Lgr5-positive (Lgr5+) stem cells induces cellular plasticity and the emergence of transient Revival stem cells (RevSCs), a process critically dependent on YAP/TAZ signaling. Conversely, the stomach utilizes paligenosis, where quiescent p57-positive (p57+) mature chief cells act as reserve stem cells, dedifferentiating to restore damaged tissue. Although the cellular origins differ, both organs appear to share some common regenerative features, including transient activation of pro-proliferative programs such as YAP/TAZ signaling. In contrast, whether Retinoic Acid (RA) signaling also serves as a conserved mechanism for regenerative resolution in the stomach remains to be determined. In this review, we discuss the cellular and molecular mechanisms governing regeneration in these two organs. This comparative analysis provides a framework for future research.
    DOI:  https://doi.org/10.1016/j.gde.2026.102515
  12. Cell Syst. 2026 Jul 15. pii: S2405-4712(26)00154-7. [Epub ahead of print]17(7): 101672
    Programmable regenerative tissues: Converging mammalian synthetic biology and tissue engineering.
    Alexander E Vlahos.
      Synthetic biology can program cellular behavior but remains underused in regenerative medicine. This commentary argues that integrating synthetic biology with tissue engineering should target vascularization and immune integration through compact, context-aware circuits. Embedded within engineered tissues, these circuits could enable adaptive grafts that sense stress and coordinate regenerative responses.
    DOI:  https://doi.org/10.1016/j.cels.2026.101672
  13. Nat Biotechnol. 2026 Jul;44(7): 1099
    Bispecific antibodies.
      
    DOI:  https://doi.org/10.1038/s41587-026-03205-1
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒27 at 19:47.