bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–02–23
eight papers selected by
Xiao Qin, University of Oxford
  1. Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
  2. Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation.
  3. Tracking protein binding to cis-regulatory elements with PRINT.
  4. What is the main bottleneck in deriving biological understanding from spatial transcriptomic profiling?
  5. Cancer evolution could inform targets for personalized anticancer vaccines.
  6. A unified analysis of atlas single cell data.
  7. The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.
  8. What are the best AI tools for research? Nature's guide.
  1. Cell Stem Cell. 2025 Feb 13. pii: S1934-5909(25)00011-6. [Epub ahead of print]
    Sustained NF-κB activation allows mutant alveolar stem cells to co-opt a regeneration program for tumor initiation.
    Frances J England, Ignacio Bordeu, Minn-E Ng, JaeHak Bang, Bumsoo Kim, Jinwook Choi, Erik C Cardoso, Bon-Kyoung Koo, Benjamin D Simons, Joo-Hyeon Lee.
      Disruptions to regulatory signals governing stem cell fate open the pathway to tumorigenesis. To determine how these programs become destabilized, we fate-map thousands of murine wild-type and KrasG12D-mutant alveolar type II (AT2) stem cells in vivo and find evidence for two independent AT2 subpopulations marked by distinct tumorigenic capacities. By combining clonal analyses with single-cell transcriptomics, we unveil striking parallels between lung regeneration and tumorigenesis that implicate Il1r1 as a common activator of AT2 reprogramming. We show that tumor evolution proceeds through the acquisition of lineage infidelity and reversible transitions between mutant states, which, in turn, modulate wild-type AT2 dynamics. Finally, we discover how sustained nuclear factor κB (NF-κB) activation sets tumorigenesis apart from regeneration, allowing mutant cells to subvert differentiation in favor of tumor growth.
    Keywords:  AT2 clone dynamics; NF-κB activation; cell fate plasticity; cell plasticity; clonal modeling; lineage tracing; lung cancer; lung stem cells; regeneration program; stem cell competition; tumor ecosystem dynamics; tumor evolution
    DOI:  https://doi.org/10.1016/j.stem.2025.01.011
  2. bioRxiv. 2025 Feb 08. pii: 2025.02.07.636917. [Epub ahead of print]
    Niche-driven phenotypic plasticity and cis-regulatory dynamics of a revised model for intestinal secretory differentiation.
    Swarnabh Bhattacharya, Guodong Tei, Pratik Narendra Pratap Singh, Ermanno Malagola, Onur Eskiocak, Ruiyang He, Judith Kraiczy, Wei Gu, Yakov Perlov, Semir Beyaz, Timothy Cragin Wang, Qiao Zhou, Ramesh Arjun Shivdasani.
      Enterocytes and four secretory cell types derive from stem cells located in intestinal crypts. Whereas secretory goblet and Paneth cells have long been considered distinct, we find high overlap in their transcripts and sites of accessible chromatin, in marked contrast to those of sibling enteroendocrine or tuft cells. Mouse and human goblet and Paneth cells express extraordinary fractions of selective antimicrobial genes, reflecting specific and variable gene responses to local niche signals. Wnt signaling retains few ATOH1+ secretory daughters in crypt bottoms, where an absence of BMP signaling potently induces Paneth features; those that move away from crypt bottoms acquire classic goblet properties. These post-mitotic cellular phenotypes and their underlying accessible cis-elements interconvert readily. Thus, goblet and Paneth properties represent alternative manifestations of a single versatile signal-responsive secretory cell. These findings reveal exquisite niche-dependent cell plasticity and the cis-regulatory dynamics of an updated unitarian model of the intestinal epithelial lineage.
    DOI:  https://doi.org/10.1101/2025.02.07.636917
  3. Nat Rev Genet. 2025 Feb 21.
    Tracking protein binding to cis-regulatory elements with PRINT.
    Yan Hu.
      
    DOI:  https://doi.org/10.1038/s41576-025-00823-4
  4. Cell Syst. 2025 Feb 19. pii: S2405-4712(25)00033-X. [Epub ahead of print]16(2): 101200
    What is the main bottleneck in deriving biological understanding from spatial transcriptomic profiling?
    Jeffrey R Moffitt, Mingyao Li, Qing Nie, Kazumasa Kanemaru, Sarah A Teichmann, Daniel Dar, Luciane T Kagohara, Shalev Itzkovitz, Roser Vento-Tormo, Itai Yanai, Elana J Fertig, Fabian J Theis.
      
    DOI:  https://doi.org/10.1016/j.cels.2025.101200
  5. Nature. 2025 Feb 21.
    Cancer evolution could inform targets for personalized anticancer vaccines.
      
    Keywords:  Cancer; Health care; Vaccines
    DOI:  https://doi.org/10.1038/d41586-025-00467-8
  6. Genome Res. 2025 Feb 18. pii: gr.279631.124. [Epub ahead of print]
    A unified analysis of atlas single cell data.
    Hao Chen, Nam D Nguyen, Matt Ruffalo, Ziv Y Bar-Joseph.
      Recent efforts to generate atlas-scale single-cell data provide opportunities for joint analysis across tissues and modalities. Existing methods use cells as the reference unit, hindering downstream gene-based analysis and removing genuine biological variations. Here we present GIANT, an integration method designed for atlas-scale gene analysis across cell types and tissues. GIANT converts datasets into gene graphs and recursively embeds genes without additional alignment. Applying GIANT to two recent atlas datasets yields unified gene embedding spaces across human tissues and data modalities. Further evaluations demonstrate GIANT's usefulness in discovering diverse gene functions and underlying gene regulations in cells from different tissues.
    DOI:  https://doi.org/10.1101/gr.279631.124
  7. Cell Rep. 2025 Feb 11. pii: S2211-1247(25)00057-9. [Epub ahead of print] 115286
    The balance between IFN-γ and ERK/MAPK signaling activities ensures lifelong maintenance of intestinal stem cells.
    May Nakajima-Koyama, Mio Kabata, Joonseong Lee, Yuko Sogabe, Satoko Sakurai, Akira Hirota, Mizuki Kimura, Tomonori Nakamura, Yusuke Imoto, Kohei Kometani, Yoko Hamazaki, Yasuaki Hiraoka, Mitinori Saitou, Eisuke Nishida, Takuya Yamamoto.
      While the intestinal epithelium has the highest cellular turnover rates in the mammalian body, it is also considered one of the tissues most resilient to aging-related disorders. Here, we reveal an innate protective mechanism that safeguards intestinal stem cells (ISCs) from environmental conditions in the aged intestine. Using in vivo phenotypic analysis, transcriptomics, and in vitro intestinal organoid studies, we show that age-dependent activation of interferon-γ (IFN-γ) signaling and inactivation of extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling are responsible for establishing an equilibrium of Lgr5+ ISCs-between active and quiescent states-to preserve the ISC pool during aging. Furthermore, we show that differentiated cells have different sensitivities to each of the two signaling pathways, which may induce aging-related, functional, and metabolic changes in the body. Thus, our findings reveal an exquisitely balanced, age-dependent signaling mechanism that preserves stem cells at the expense of differentiated cells.
    Keywords:  CP: Stem cell research; ERK/MAPK signaling pathway; IFN-γ signaling pathway; aging; intestinal stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2025.115286
  8. Nature. 2025 Feb 17.
    What are the best AI tools for research? Nature's guide.
    Elizabeth Gibney.
      
    Keywords:  Language; Machine learning; Software
    DOI:  https://doi.org/10.1038/d41586-025-00437-0
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