bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2025–03–02
ten papers selected by
Xiao Qin, University of Oxford
  1. Genome-coverage single-cell histone modifications for embryo lineage tracing.
  2. Systematic reconstruction of molecular pathway signatures using scalable single-cell perturbation screens.
  3. An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration.
  4. Decoding heterogeneous single-cell perturbation responses.
  5. Anti-resonance in developmental signaling regulates cell fate decisions.
  6. Current and future perspectives in the management and treatment of colorectal cancer.
  7. Molecular mechanisms altering cell identity in cancer.
  8. Endoscopic approach to large non-pedunculated colorectal polyps.
  9. Accuracy and long-term effectiveness of established screening modalities and strategies in colorectal cancer screening: An umbrella review.
  10. Mass-spectrometry-based proteomics: from single cells to clinical applications.
  1. Nature. 2025 Feb 26.
    Genome-coverage single-cell histone modifications for embryo lineage tracing.
    Min Liu, Yanzhu Yue, Xubin Chen, Kexin Xian, Chao Dong, Ming Shi, Haiqing Xiong, Kang Tian, Yuzhe Li, Qiangfeng Cliff Zhang, Aibin He.
      Substantial epigenetic resetting during early embryo development from fertilization to blastocyst formation ensures zygotic genome activation and leads to progressive cellular heterogeneities1-3. Mapping single-cell epigenomic profiles of core histone modifications that cover each individual cell is a fundamental goal in developmental biology. Here we develop target chromatin indexing and tagmentation (TACIT), a method that enabled genome-coverage single-cell profiling of seven histone modifications across mouse early embryos. We integrated these single-cell histone modifications with single-cell RNA sequencing data to chart a single-cell resolution epigenetic landscape. Multimodal chromatin-state annotations showed that the onset of zygotic genome activation at the early two-cell stage already primes heterogeneities in totipotency. We used machine learning to identify totipotency gene regulatory networks, including stage-specific transposable elements and putative transcription factors. CRISPR activation of a combination of these identified transcription factors induced totipotency activation in mouse embryonic stem cells. Together with single-cell co-profiles of multiple histone modifications, we developed a model that predicts the earliest cell branching towards the inner cell mass and the trophectoderm in latent multimodal space and identifies regulatory elements and previously unknown lineage-specifying transcription factors. Our work provides insights into single-cell epigenetic reprogramming, multimodal regulation of cellular lineages and cell-fate priming during mouse pre-implantation development.
    DOI:  https://doi.org/10.1038/s41586-025-08656-1
  2. Nat Cell Biol. 2025 Feb 26.
    Systematic reconstruction of molecular pathway signatures using scalable single-cell perturbation screens.
    Longda Jiang, Carol Dalgarno, Efthymia Papalexi, Isabella Mascio, Hans-Hermann Wessels, Huiyoung Yun, Nika Iremadze, Gila Lithwick-Yanai, Doron Lipson, Rahul Satija.
      Recent advancements in functional genomics have provided an unprecedented ability to measure diverse molecular modalities, but predicting causal regulatory relationships from observational data remains challenging. Here, we leverage pooled genetic screens and single-cell sequencing (Perturb-seq) to systematically identify the targets of signalling regulators in diverse biological contexts. We demonstrate how Perturb-seq is compatible with recent and commercially available advances in combinatorial indexing and next-generation sequencing, and perform more than 1,500 perturbations split across six cell lines and five biological signalling contexts. We introduce an improved computational framework (Mixscale) to address cellular variation in perturbation efficiency, alongside optimized statistical methods to learn differentially expressed gene lists and conserved molecular signatures. Finally, we demonstrate how our Perturb-seq derived gene lists can be used to precisely infer changes in signalling pathway activation for in vivo and in situ samples. Our work enhances our understanding of signalling regulators and their targets, and lays a computational framework towards the data-driven inference of an 'atlas' of perturbation signatures.
    DOI:  https://doi.org/10.1038/s41556-025-01622-z
  3. Development. 2025 Feb 27. pii: dev.204654. [Epub ahead of print]
    An Lgr5-independent developmental lineage is involved in mouse intestinal regeneration.
    Maryam Marefati, Valeria Fernandez-Vallone, Morgane Leprovots, Gabriella Vasile, Frédérick Libert, Anne Lefort, Gilles Dinsart, Achim Weber, Jasna Jetzer, Marie-Isabelle Garcia, Gilbert Vassart.
      Collagenase/dispase treatment of intestinal tissue from adult mice generates cells growing in matrigel as stably replatable cystic spheroids in addition to differentiated organoids. Contrary to classical EDTA-derived organoids, these spheroids display poor intestinal differentiation and are independent of Rspondin/Noggin/EGF for growth. Their transcriptome resembles strikingly that of fetal intestinal spheroids, with downregulation of crypt base columnar cell (CBC) markers (Lgr5, Ascl2, Smoc2, Olfm4). In addition, they display upregulation of inflammatory and mesenchymal genetic programs, together with robust expression of YAP target genes. Lineage tracing, cell-sorting and single cell RNA sequencing experiments demonstrate that adult spheroid-generating cells belong to a hitherto undescribed developmental lineage, independent of Lgr5+ve CBCs, and are involved in regeneration of the epithelium following CBC ablation.
    Keywords:  Intestinal development; Organoids; Regeneration; Stem cells
    DOI:  https://doi.org/10.1242/dev.204654
  4. Nat Cell Biol. 2025 Feb 26.
    Decoding heterogeneous single-cell perturbation responses.
    Bicna Song, Dingyu Liu, Weiwei Dai, Natalie F McMyn, Qingyang Wang, Dapeng Yang, Adam Krejci, Anatoly Vasilyev, Nicole Untermoser, Anke Loregger, Dongyuan Song, Breanna Williams, Bess Rosen, Xiaolong Cheng, Lumen Chao, Hanuman T Kale, Hao Zhang, Yarui Diao, Tilmann Bürckstümmer, Janet D Siliciano, Jingyi Jessica Li, Robert F Siliciano, Danwei Huangfu, Wei Li.
      Understanding how cells respond differently to perturbation is crucial in cell biology, but existing methods often fail to accurately quantify and interpret heterogeneous single-cell responses. Here we introduce the perturbation-response score (PS), a method to quantify diverse perturbation responses at a single-cell level. Applied to single-cell perturbation datasets such as Perturb-seq, PS outperforms existing methods in quantifying partial gene perturbations. PS further enables single-cell dosage analysis without needing to titrate perturbations, and identifies 'buffered' and 'sensitive' response patterns of essential genes, depending on whether their moderate perturbations lead to strong downstream effects. PS reveals differential cellular responses on perturbing key genes in contexts such as T cell stimulation, latent HIV-1 expression and pancreatic differentiation. Notably, we identified a previously unknown role for the coiled-coil domain containing 6 (CCDC6) in regulating liver and pancreatic cell fate decisions. PS provides a powerful method for dose-to-function analysis, offering deeper insights from single-cell perturbation data.
    DOI:  https://doi.org/10.1038/s41556-025-01626-9
  5. bioRxiv. 2025 Feb 11. pii: 2025.02.04.636331. [Epub ahead of print]
    Anti-resonance in developmental signaling regulates cell fate decisions.
    Samuel J Rosen, Olivier Witteveen, Naomi Baxter, Ryan S Lach, Marianne Bauer, Maxwell Z Wilson.
      Cells process dynamic signaling inputs to regulate fate decisions during development. While oscillations or waves in key developmental pathways, such as Wnt, have been widely observed, the principles governing how cells decode these signals remain unclear. By leveraging optogenetic control of the Wnt signaling pathway in both HEK293T cells and H9 human embryonic stem cells, we systematically map the relationship between signal frequency and downstream pathway activation. We find that cells exhibit a minimal response to Wnt at certain frequencies, a behavior we term anti-resonance. We developed both detailed biochemical and simplified hidden variable models that explain how anti-resonance emerges from the interplay between fast and slow pathway dynamics. Remarkably, we find that frequency directly influences cell fate decisions involved in human gastrulation; signals delivered at anti-resonant frequencies result in dramatically reduced mesoderm differentiation. Our work reveals a previously unknown mechanism of how cells decode dynamic signals and how anti-resonance may filter against spurious activation. These findings establish new insights into how cells decode dynamic signals with implications for tissue engineering, regenerative medicine, and cancer biology.
    DOI:  https://doi.org/10.1101/2025.02.04.636331
  6. World J Clin Oncol. 2025 Feb 24. 16(2): 100807
    Current and future perspectives in the management and treatment of colorectal cancer.
    Sigfredo E Romero-Zoghbi, Evita Krumina, Fernando López-Campos, Felipe Couñago.
      In this editorial, we reviewed the article by Fadlallah et al that was recently published in the World Journal of Clinical Oncology. The article provided a comprehensive and in-depth view of the management and treatment of colorectal cancer (CRC), one of the leading causes of cancer-related morbidity and mortality worldwide. The article analyzed the therapeutic modalities and their sequencing, focusing on total neoadjuvant therapy for locally advanced rectal cancer. It highlighted the role of immunotherapy in tumors with high microsatellite instability or deficient mismatch repair, addressing recent advances that have improved prognosis and therapeutic response in localized and metastatic CRC. Innovations in surgical techniques, advanced radiotherapy, and systemic agents targeting specific mutational profiles are also discussed, reflecting on how they revolutionized clinical management. Circulating tumor DNA has emerged as a promising tool for detecting minimal residual disease, prognosis, and therapeutic monitoring, solidifying its role in precision oncology. This review emphasized the importance of technological and therapeutic advancements in improving clinical outcomes and personalizing CRC treatment.
    Keywords:  Chemoradiotherapy; Chemotherapy; Colon surgery; Colorectal cancer; Immunotherapy; Metastatic colorectal cancer; Rectal surgery; Total neoadjuvant therapy
    DOI:  https://doi.org/10.5306/wjco.v16.i2.100807
  7. Oncogene. 2025 Feb 26.
    Molecular mechanisms altering cell identity in cancer.
    Alessio Zippo, Sven Beyes.
      Intrinsic and extrinsic factors influence cancer cell identity throughout its lifespan. During tumor progression and metastasis formation, cancer cells are exposed to different environmental stimuli, resulting in a stepwise cellular reprogramming. Similar stepwise changes of cell identity have been shown as a major consequence of cancer treatment, as cells are exposed to extracellular stress that can result in the establishment of subpopulations exhibiting different epigenetic and transcriptional patterns, indicating a rapid adaptation mechanism of cellular identity by extrinsic stress factors. Both mechanisms, tumor progression-mediated changes and therapy response, rely on signaling pathways affecting the epigenetic and subsequent transcriptional landscape, which equip the cells with mechanisms for survival and tumor progression. These non-genetic alterations are propagated to the daughter cells, indicating a need for successful information propagation and transfer to the daughter generations, thereby allowing for a stepwise adaptation to environmental cues. However, the exact mechanisms how these cell identity changes are occurring, which context-specific mechanisms are behind and how this can be exploited for future therapeutic interventions is not yet fully understood and exploited. In this review, we discuss the current knowledge on cell identity maintenance mechanisms intra- and intergenerational in development and disease and how these mechanisms are altered in cancer. We will as well address how cancer treatment might target these properties.
    DOI:  https://doi.org/10.1038/s41388-025-03314-2
  8. J Can Assoc Gastroenterol. 2025 Mar;8(Suppl 2): S62-S73
    Endoscopic approach to large non-pedunculated colorectal polyps.
    Sunil Gupta, Tony He, Jeffrey D Mosko.
      Large non-pedunculated colorectal polyps ≥20 mm (LNPCPs) constitute approximately 1% of all colorectal polyps and present a spectrum of risks, including overt and covert submucosal invasive cancer (T1 colorectal cancer (CRC)). Importantly, a curative resection may be achieved for LNPCPs with superficial T1 CRC (T1a or T1b <1000 µm into submucosa), if an enbloc R0 excision (clear margins) with favourable histology is achieved (ie, absence of high-grade tumour budding, lympho-vascular invasion, and poor differentiation). Thus, while consensus recommendations advocate for endoscopic resection as the primary treatment option for LNPCPs, thorough optical assessment is imperative for selecting the most suitable ER strategy. In this review, we highlight the critical components of optical evaluation that assist in predicting the risk of T1 CRC, including morphology (Paris and LST classifications), surface pit/vascular pattern (JNET and Kudo classifications), and lesion location. Different resection modalities, including endoscopic submucosal dissection and endoscopic mucosal resection are discussed, along with important considerations that may influence the resection strategy of choice, such as access to the LNPCP and submucosal fibrosis.
    Keywords:  endoscopic mucosal resection; endoscopic submucosal dissection; large non-pedunculated colorectal polyps
    DOI:  https://doi.org/10.1093/jcag/gwae030
  9. Int J Cancer. 2025 Feb 25.
    Accuracy and long-term effectiveness of established screening modalities and strategies in colorectal cancer screening: An umbrella review.
    Yuelun Zhang, Kai Song, Yueyang Zhou, Yuqing Chen, Xinran Cheng, Min Dai, Dong Wu, Hongda Chen.
      Colorectal cancer (CRC) screening may reduce the disease incidence and mortality. However, there is a lack of comprehensive evaluation of the existing evidence on different screening modalities. We aimed to systematically summarize the diagnostic accuracy and long-term effectiveness of CRC screening. Medline, Embase, and the Cochrane Database of Systematic Reviews were searched from database inception to December 31, 2023. Systematic reviews and meta-analyses of the diagnostic accuracy of colonoscopy, flexible sigmoidoscopy (FS), guaiac-based fecal occult blood test (gFOBT), fecal immunochemical test (FIT), multi-target stool DNA (mt-sDNA) testing, plasma Septin9 methylation (mSEPT9), computed tomography colonography (CTC) using colonoscopy as the reference standard, or evaluating the long-term effectiveness of incidence and mortality of CRC screening strategies were eligible. Combined accuracy and long-term effectiveness were extracted. The level of evidence was evaluated using GRADE. Using colonoscopy as the reference standard, CTC had the highest sensitivity for detecting CRC and precursors, followed by mt-sDNA, FIT, mSEPT9, and gFOBT, all of which had satisfying specificities (>85%). Convincing evidence showed FS screening reduced CRC incidence and CRC-related mortality, and gFOBT screening reduced CRC mortality but not incidence. Moderate evidence suggested colonoscopy and FIT screening were associated with reduced CRC incidence and mortality. CRC screening was not associated with the reduction of all-cause mortality and non-CRC mortality. Strong variations of diagnostic accuracy existed for the established non-invasive CRC screening methods. Consistent evidence demonstrated the effectiveness of screening in preventing CRC-related death, but convincing evidence was restricted to FS and gFOBT.
    Keywords:  accuracy; colorectal cancer; effectiveness; screening
    DOI:  https://doi.org/10.1002/ijc.35381
  10. Nature. 2025 Feb;638(8052): 901-911
    Mass-spectrometry-based proteomics: from single cells to clinical applications.
    Tiannan Guo, Judith A Steen, Matthias Mann.
      Mass-spectrometry (MS)-based proteomics has evolved into a powerful tool for comprehensively analysing biological systems. Recent technological advances have markedly increased sensitivity, enabling single-cell proteomics and spatial profiling of tissues. Simultaneously, improvements in throughput and robustness are facilitating clinical applications. In this Review, we present the latest developments in proteomics technology, including novel sample-preparation methods, advanced instrumentation and innovative data-acquisition strategies. We explore how these advances drive progress in key areas such as protein-protein interactions, post-translational modifications and structural proteomics. Integrating artificial intelligence into the proteomics workflow accelerates data analysis and biological interpretation. We discuss the application of proteomics to single-cell analysis and spatial profiling, which can provide unprecedented insights into cellular heterogeneity and tissue architecture. Finally, we examine the transition of proteomics from basic research to clinical practice, including biomarker discovery in body fluids and the promise and challenges of implementing proteomics-based diagnostics. This Review provides a broad and high-level overview of the current state of proteomics and its potential to revolutionize our understanding of biology and transform medical practice.
    DOI:  https://doi.org/10.1038/s41586-025-08584-0
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