bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–12–01
eightteen papers selected by
Xiao Qin, University of Oxford
  1. Why tumour geography matters - and how to map it.
  2. Generalized AI models for genomics applications.
  3. The lives of cells, recorded.
  4. Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells.
  5. Association of epigenetic landscapes with heterogeneity and plasticity in pancreatic cancer.
  6. Understanding cancer from a biophysical, developmental and systems biology perspective using the landscapes-attractor model.
  7. Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility.
  8. Moving towards more personalized approaches in locally advanced and metastatic colorectal cancer.
  9. Mapping enhancer-gene regulatory interactions from single-cell data.
  10. Multilevel Intervention and Outreach for Colorectal Cancer Screening.
  11. Spatially Resolved in vivo CRISPR Screen Sequencing via Perturb-DBiT.
  12. A platform for multimodal in vivo pooled genetic screens reveals regulators of liver function.
  13. PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance.
  14. Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand?
  15. A panoramic view of cell population dynamics in mammalian aging.
  16. FZD5 controls intestinal crypt homeostasis and colonic Wnt surrogate agonist response.
  17. Development of an inducible DNA barcoding system to understand lineage changes in Arabidopsis regeneration.
  18. Split-pool barcoding serves up an epigenomic smorgasbord.
  1. Nature. 2024 Nov;635(8040): 1031-1033
    Why tumour geography matters - and how to map it.
    Michael Eisenstein.
      
    Keywords:  Cancer; Proteomics; Technology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-024-03830-3
  2. Nat Methods. 2024 Nov 28.
    Generalized AI models for genomics applications.
      
    DOI:  https://doi.org/10.1038/s41592-024-02524-y
  3. Nat Rev Genet. 2024 Nov 25.
    The lives of cells, recorded.
    Amjad Askary, Wei Chen, Junhong Choi, Lucia Y Du, Michael B Elowitz, James A Gagnon, Alexander F Schier, Sophie Seidel, Jay Shendure, Tanja Stadler, Martin Tran.
      A paradigm for biology is emerging in which cells can be genetically programmed to write their histories into their own genomes. These records can subsequently be read, and the cellular histories reconstructed, which for each cell could include a record of its lineage relationships, extrinsic influences, internal states and physical locations, over time. DNA recording has the potential to transform the way that we study developmental and disease processes. Recent advances in genome engineering are driving the development of systems for DNA recording, and meanwhile single-cell and spatial omics technologies increasingly enable the recovery of the recorded information. Combined with advances in computational and phylogenetic inference algorithms, the DNA recording paradigm is beginning to bear fruit. In this Perspective, we explore the rationale and technical basis of DNA recording, what aspects of cellular biology might be recorded and how, and the types of discovery that we anticipate this paradigm will enable.
    DOI:  https://doi.org/10.1038/s41576-024-00788-w
  4. Curr Opin Cell Biol. 2024 Nov 27. pii: S0955-0674(24)00124-8. [Epub ahead of print]92 102445
    Design principles of regulatory networks underlying epithelial mesenchymal plasticity in cancer cells.
    Sarthak Sahoo, Kishore Hari, Mohit Kumar Jolly.
      Phenotypic plasticity is a hallmark of cancer and drives metastatic disease and drug resistance. The dynamics of epithelial mesenchymal plasticity is driven by complex interactions involving multiple feedback loops in underlying networks operating at multiple regulatory levels such as transcriptional and epigenetic. The past decade has witnessed a surge in systems level analysis of structural and dynamical traits of these networks. Here, we highlight the key insights elucidated from such efforts-a) multistability in gene regulatory networks and the co-existence of many hybrid phenotypes, thus enabling a landscape with multiple 'attractors', b) mutually antagonistic 'teams' of genes in these networks, shaping the rates of cell state transition in this landscape, and c) chromatin level changes that can alter the landscape, thus controlling reversibility of cell state transitions, allowing cellular memory in the context of epithelial mesenchymal plasticity in cancer cells. Such approaches, in close integration with high-throughput longitudinal data, have improved our understanding of the dynamics of cell state transitions implicated in tumor cell plasticity.
    Keywords:  Attractor; Epigenetic memory; Epithelial-Mesenchymal Transition; Multistability; Phenotypic plasticity
    DOI:  https://doi.org/10.1016/j.ceb.2024.102445
  5. Crit Rev Oncol Hematol. 2024 Nov 22. pii: S1040-8428(24)00316-0. [Epub ahead of print]206 104573
    Association of epigenetic landscapes with heterogeneity and plasticity in pancreatic cancer.
    Paul Manoukian, Leo C Kuhnen, Hanneke W M van Laarhoven, Maarten F Bijlsma.
      Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Due to a lack of clear symptoms, patients often present with advanced disease, with limited clinical intervention options. The high mortality rate of PDAC is, however, also a result of several other factors that include a high degree of heterogeneity and treatment resistant cellular phenotypes. Molecular subtypes of PDAC have been identified that are thought to represent cellular phenotypes at the tissue level. The epigenetic landscape is an important factor that dictates these subtypes. Permissive epigenetic landscapes serve as drivers of molecular heterogeneity and cellular plasticity in developing crypts as well as metaplastic lesions. Drawing parallels with other cancers, we hypothesize that epigenetic permissiveness is a potential driver of cellular plasticity in PDAC. In this review will explore the epigenetic alterations that underlie PDAC cell states and relate them to cellular plasticity from other contexts. In doing so, we aim to highlight epigenomic drivers of PDAC heterogeneity and plasticity and, with that, offer some insight to guide pre-clinical research.
    Keywords:  Cell state; Epigenetics; Heterogeneity; Hybrid chromatin states; Pancreatic ductal adenocarcinoma; Plasticity
    DOI:  https://doi.org/10.1016/j.critrevonc.2024.104573
  6. Biosystems. 2024 Nov 22. pii: S0303-2647(24)00261-2. [Epub ahead of print]247 105376
    Understanding cancer from a biophysical, developmental and systems biology perspective using the landscapes-attractor model.
    Thomas W Grunt.
      Biophysical, developmental and systems-biology considerations enable deeper understanding why cancer is life threatening despite intensive research. Here we use two metaphors. Both conceive the cell genome and the encoded molecular system as an interacting gene regulatory network (GRN). According to Waddington's epigenetic (quasi-potential)-landscape, an instrumental tool in ontogenetics, individual interaction patterns ( = expression profiles) within this GRN represent possible cell states with different stabilities. Network interactions with low stability are represented on peaks. Unstable interactions strive towards regions with higher stability located at lower altitude in valleys termed attractors that correspond to stable cell phenotypes. Cancer cells are seen as GRNs adopting aberrant semi-stable attractor states (cancer attractor). In the second metaphor, Wright's phylogenetic fitness (adaptive) landscape, each genome ( = GRN) is assigned a specific position in the landscape according to its structure and reproductive fitness in the specific environment. High elevation signifies high fitness and low altitude low fitness. Selection ensures that mutant GRNs evolve and move from valleys to peaks. The genetic flexibility is highlighted in the fitness landscape, while non-genetic flexibility is captured in the quasi-potential landscape. These models resolve several inconsistencies that have puzzled cancer researchers, such as the fact that phenotypes generated by non-genetic mechanisms coexist in a single tumor with phenotypes caused by mutations and they mitigate conflicts between cancer theories that claim cancer is caused by mutation (somatic mutation theory) or by disruption of tissue architecture (tissue organization field theory). Nevertheless, spontaneous mutations play key roles in cancer. Remarkable, fundamental natural laws such as the second law of thermodynamics and quantum mechanics state that mutations are inevitable events. The good side of this is that without mutational variability in DNA, evolutionary development would not have occurred, but its bad side is that the occurrence of cancer is essentially inevitable. In summary, both landscapes together fully describe the behavior of cancer under normal and stressful conditions such as chemotherapy. Thus, the landscapes-attractor model fully describes cancer cell behavior and offers new perspectives for future treatment.
    Keywords:  Cancer attractor; Entropy; Epigenetic landscape; Fitness landscape; Mutation; Quantum biology
    DOI:  https://doi.org/10.1016/j.biosystems.2024.105376
  7. Dev Cell. 2024 Nov 15. pii: S1534-5807(24)00661-0. [Epub ahead of print]
    Frizzled5 controls murine intestinal epithelial cell plasticity through organization of chromatin accessibility.
    Lu Deng, Xi C He, Shiyuan Chen, Ning Zhang, Fengyan Deng, Allison Scott, Yanfeng He, Dai Tsuchiya, Sarah E Smith, Michael Epp, Seth Malloy, Fang Liu, Mark Hembree, Qinghui Mu, Jeffrey S Haug, Ermanno Malagola, Huzaifa Hassan, Kaitlyn Petentler, Rhonda Egidy, Lucinda Maddera, Jonathon Russell, Yan Wang, Hua Li, Chongbei Zhao, Anoja Perera, Timothy C Wang, Calvin J Kuo, Linheng Li.
      The homeostasis of the intestinal epithelium relies on intricate yet insufficiently understood mechanisms of intestinal epithelial plasticity. Here, we elucidate the pivotal role of Frizzled5 (Fzd5), a Wnt pathway receptor, as a determinant of murine intestinal epithelial cell fate. Deletion of Fzd5 in Lgr5+ intestinal stem cells (ISCs) impairs their self-renewal, whereas its deletion in Krt19+ cells disrupts lineage generation, without affecting crypt integrity in either case. However, a broader deletion of Fzd5 across the epithelium leads to substantial crypt deterioration. Integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell ATAC-seq (scATAC-seq) identifies that Fzd5 governs chromatin accessibility, orchestrating the regulation of stem- and lineage-related gene expression mainly in ISCs and progenitor cells. In summary, our findings provide insights into the regulatory role of Fzd5 in governing intestinal epithelial plasticity.
    Keywords:  Fzd5; Wnt pathway; chromatin accessibility; intestinal stem cell; plasticity; single-cell transcriptome and epigenome
    DOI:  https://doi.org/10.1016/j.devcel.2024.10.021
  8. Nat Rev Gastroenterol Hepatol. 2024 Nov 28.
    Moving towards more personalized approaches in locally advanced and metastatic colorectal cancer.
    Chelsie K Sievers, Cathy Eng.
      
    DOI:  https://doi.org/10.1038/s41575-024-01025-9
  9. bioRxiv. 2024 Nov 24. pii: 2024.11.23.624931. [Epub ahead of print]
    Mapping enhancer-gene regulatory interactions from single-cell data.
    Maya U Sheth, Wei-Lin Qiu, X Rosa Ma, Andreas R Gschwind, Evelyn Jagoda, Anthony S Tan, Hjörleifur Einarsson, Bram L Gorissen, Danilo Dubocanin, Christopher S McGinnis, Dulguun Amgalan, Ansuman T Satpathy, Thouis R Jones, Lars M Steinmetz, Anshul Kundaje, Berk Ustun, Jesse M Engreitz, Robin Andersson.
      Mapping enhancers and their target genes in specific cell types is crucial for understanding gene regulation and human disease genetics. However, accurately predicting enhancer-gene regulatory interactions from single-cell datasets has been challenging. Here, we introduce a new family of classification models, scE2G, to predict enhancer-gene regulation. These models use features from single-cell ATAC-seq or multiomic RNA and ATAC-seq data and are trained on a CRISPR perturbation dataset including >10,000 evaluated element-gene pairs. We benchmark scE2G models against CRISPR perturbations, fine-mapped eQTLs, and GWAS variant-gene associations and demonstrate state-of-the-art performance at prediction tasks across multiple cell types and categories of perturbations. We apply scE2G to build maps of enhancer-gene regulatory interactions in heterogeneous tissues and interpret noncoding variants associated with complex traits, nominating regulatory interactions linking INPP4B and IL15 to lymphocyte counts. The scE2G models will enable accurate mapping of enhancer-gene regulatory interactions across thousands of diverse human cell types.
    DOI:  https://doi.org/10.1101/2024.11.23.624931
  10. JAMA Netw Open. 2024 Nov 04. 7(11): e2446703
    Multilevel Intervention and Outreach for Colorectal Cancer Screening.
    Aasma Shaukat.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2024.46703
  11. bioRxiv. 2024 Nov 19. pii: 2024.11.18.624106. [Epub ahead of print]
    Spatially Resolved in vivo CRISPR Screen Sequencing via Perturb-DBiT.
    Alev Baysoy, Xiaolong Tian, Feifei Zhang, Paul Renauer, Zhiliang Bai, Hao Shi, Haikuo Li, Bo Tao, Mingyu Yang, Archibald Enninful, Fu Gao, Guangchuan Wang, Wanqiu Zhang, Thao Tran, Nathan Heath Patterson, Shuozhen Bao, Chuanpeng Dong, Shan Xin, Mei Zhong, Sherri Rankin, Cliff Guy, Yan Wang, Jon P Connelly, Shondra M Pruett-Miller, Hongbo Chi, Sidi Chen, Rong Fan.
      Perturb-seq enabled the profiling of transcriptional effects of genetic perturbations in single cells but lacks the ability to examine the impact on tissue environments. We present Perturb-DBiT for simultaneous co- sequencing of spatial transcriptome and guide RNAs (gRNAs) on the same tissue section for in vivo CRISPR screen with genome-scale gRNA libraries, offering a comprehensive understanding of how genetic modifications affect cellular behavior and tissue architecture. This platform supports a variety of delivery vectors, gRNA library sizes, and tissue preparations, along with two distinct gRNA capture methods, making it adaptable to a wide range of experimental setups. In applying Perturb-DBiT, we conducted un-biased knockouts of tens of genes or at genome-wide scale across three cancer models. We mapped all gRNAs in individual colonies and corresponding transcriptomes in a human cancer metastatic colonization model, revealing clonal dynamics and cooperation. We also examined the effect of genetic perturbation on the tumor immune microenvironment in an immune-competent syngeneic model, uncovering differential and synergistic perturbations in promoting immune infiltration or suppression in tumors. Perturb-DBiT allows for simultaneously evaluating the impact of each knockout on tumor initiation, development, metastasis, histopathology, and immune landscape. Ultimately, it not only broadens the scope of genetic inquiry, but also lays the groundwork for developing targeted therapeutic strategies.
    DOI:  https://doi.org/10.1101/2024.11.18.624106
  12. bioRxiv. 2024 Nov 21. pii: 2024.11.18.624217. [Epub ahead of print]
    A platform for multimodal in vivo pooled genetic screens reveals regulators of liver function.
    Reuben A Saunders, William E Allen, Xingjie Pan, Jaspreet Sandhu, Jiaqi Lu, Thomas K Lau, Karina Smolyar, Zuri A Sullivan, Catherine Dulac, Jonathan S Weissman, Xiaowei Zhuang.
      Organ function requires coordinated activities of thousands of genes in distinct, spatially organized cell types. Understanding the basis of emergent tissue function requires approaches to dissect the genetic control of diverse cellular and tissue phenotypes in vivo . Here, we develop paired imaging and sequencing methods to construct large-scale, multi-modal genotype-phenotypes maps in tissue with pooled genetic perturbations. Using imaging, we identify genetic perturbations in individual cells while simultaneously measuring their gene expression and subcellular morphology. Using single-cell sequencing, we measure transcriptomic responses to the same genetic perturbations. We apply this approach to study hundreds of genetic perturbations in the mouse liver. Our study reveals regulators of hepatocyte zonation and liver unfolded protein response, as well as distinct pathways that cause hepatocyte steatosis. Our approach enables new ways of interrogating the genetic basis of complex cellular and organismal physiology and provides crucial training data for emerging machine-learning models of cellular function.
    DOI:  https://doi.org/10.1101/2024.11.18.624217
  13. Science. 2024 Nov 29. 386(6725): eadj7615
    PIEZO-dependent mechanosensing is essential for intestinal stem cell fate decision and maintenance.
    Meryem B Baghdadi, Ronja M Houtekamer, Louisiane Perrin, Abilasha Rao-Bhatia, Myles Whelen, Linda Decker, Martin Bergert, Carlos Pérez-Gonzàlez, Réda Bouras, Giacomo Gropplero, Adrian K H Loe, Amin Afkhami-Poostchi, Xin Chen, Xi Huang, Stephanie Descroix, Jeffrey L Wrana, Alba Diz-Muñoz, Martijn Gloerich, Arshad Ayyaz, Danijela Matic Vignjevic, Tae-Hee Kim.
      Stem cells perceive and respond to biochemical and physical signals to maintain homeostasis. Yet, it remains unclear how stem cells sense mechanical signals from their niche in vivo. In this work, we investigated the roles of PIEZO mechanosensitive channels in the intestinal stem cell (ISC) niche. We used mouse genetics and single-cell RNA sequencing analysis to assess the requirement for PIEZO channels in ISC maintenance. In vivo measurement of basement membrane stiffness showed that ISCs reside in a more rigid microenvironment at the bottom of the crypt. Three-dimensional and two-dimensional organoid systems combined with bioengineered substrates and a stretching device revealed that PIEZO channels sense extracellular mechanical stimuli to modulate ISC function. This study delineates the mechanistic cascade of PIEZO activation that coordinates ISC fate decision and maintenance.
    DOI:  https://doi.org/10.1126/science.adj7615
  14. Cancers (Basel). 2024 Nov 19. pii: 3870. [Epub ahead of print]16(22):
    Precision Medicine for Metastatic Colorectal Cancer: Where Do We Stand?
    Patrick W Underwood, Timothy M Pawlik.
      Metastatic colorectal cancer is a leading cause of cancer-related death across the world. The treatment paradigm has shifted away from systemic chemotherapy alone to include targeted therapy and immunotherapy. The past two decades have been characterized by increased investigation into molecular profiling of colorectal cancer. These molecular profiles help physicians to better understand colorectal cancer biology among patients with metastatic disease. Additionally, improved data on genetic pathways allow for specific therapies to be targeted at the underlying molecular profile. Investigation of the EGFR, VEGF, HER2, and other pathways, as well as deficient mismatch repair, has led to the development of multiple targeted therapies that are now utilized in the National Comprehensive Cancer Network guidelines for colon and rectal cancer. While these new therapies have contributed to improved survival for metastatic colorectal cancer, long-term survival remains poor. Additional investigation to understand resistance to targeted therapy and development of new targeted therapy is necessary. New therapies are under development and are being tested in the preclinical and clinical settings. The aim of this review is to provide a comprehensive evaluation of molecular profiling, currently available therapies, and ongoing obstacles in the field of colorectal cancer.
    Keywords:  colon cancer; molecular profiling; personalized medicine; targeted therapy
    DOI:  https://doi.org/10.3390/cancers16223870
  15. Science. 2024 Nov 28. eadn3949
    A panoramic view of cell population dynamics in mammalian aging.
    Zehao Zhang, Chloe Schaefer, Weirong Jiang, Ziyu Lu, Jasper Lee, Andras Sziraki, Abdulraouf Abdulraouf, Brittney Wick, Maximilian Haeussler, Zhuoyan Li, Gesmira Molla, Rahul Satija, Wei Zhou, Junyue Cao.
      To elucidate aging-associated cellular population dynamics, we present PanSci, a single-cell transcriptome atlas profiling over 20 million cells from 623 mouse tissues across different life stages, sexes, and genotypes. This comprehensive dataset reveals more than 3,000 unique cellular states and over 200 aging-associated cell populations. Our panoramic analysis uncovered organ-, lineage-, and sex-specific shifts of cellular dynamics during lifespan progression. Moreover, we identify both systematic and organ-specific alterations in immune cell populations associated with aging. We further explored the regulatory roles of the immune system on aging and pinpointed specific age-related cell population expansions that are lymphocyte dependent. Our "cell-omics" strategy enhances comprehension of cellular aging and lays the groundwork for exploring the complex cellular regulatory networks in aging and aging-associated diseases.
    DOI:  https://doi.org/10.1126/science.adn3949
  16. Dev Cell. 2024 Nov 19. pii: S1534-5807(24)00662-2. [Epub ahead of print]
    FZD5 controls intestinal crypt homeostasis and colonic Wnt surrogate agonist response.
    Qinghui Mu, Andrew Ha, Antonio J M Santos, Yuan-Hung Lo, Vincent van Unen, Yi Miao, Madeline Tomaske, Veronica K Guzman, Samira Alwahabi, Jenny J Yuan, Lu Deng, Linheng Li, K Christopher Garcia, Calvin J Kuo.
      The rapidly regenerating intestinal epithelium requires crypt intestinal stem cells (ISCs). Wnt/β-catenin signaling maintains crypt homeostasis and Lgr5+ ISCs, and WNT ligands bind Frizzled receptors (FZD1-10). Identifying specific FZD(s) essential for intestinal homeostasis has been elusive; however, bioengineered antagonists blocking Wnt binding to FZD5 and FZD8 deplete the gut epithelium in vivo, highlighting potential roles. Here, an epithelial-specific Fzd5 knockout (KO) elicited lethal pan-intestinal crypt and villus loss, whereas an Lgr5+ ISC-specific Fzd5 KO depleted Lgr5+ ISCs via premature differentiation and repressed Wnt target genes. Fzd5-null phenotypes were rescued by constitutive β-catenin activation in vivo and in both mouse and human enteroids. KO of Fzd5, not Fzd8, in enteroids ablated responsiveness to dual-specificity FZD5/FZD8-selective Wnt surrogate agonists, which ameliorated DSS-induced colitis in wild-type and Fzd8 KO mice. Overall, FZD5 is a dominant and essential regulator of crypt homeostasis, Lgr5+ ISCs, and intestinal response to Wnt surrogate agonists, with implications for therapeutic mucosal repair.
    Keywords:  Fzd5; Lgr5; Wnt signaling; colitis; intestinal stem cells
    DOI:  https://doi.org/10.1016/j.devcel.2024.10.022
  17. Dev Cell. 2024 Nov 19. pii: S1534-5807(24)00663-4. [Epub ahead of print]
    Development of an inducible DNA barcoding system to understand lineage changes in Arabidopsis regeneration.
    Xinyue Lu, Qiyan Zhang, Zejia Wang, Xuanzhi Cheng, Huiru Yan, Shuyi Cai, Huawei Zhang, Qikun Liu.
      Plants demonstrate a high degree of developmental plasticity, capable of regenerating entire individuals from detached somatic tissues-a regenerative phenomenon rarely observed in metazoa. Consequently, elucidating the lineage relationship between somatic founder cells and descendant cells in regenerated plant organs has long been a pursuit. In this study, we developed and optimized both DNA barcode- and multi-fluorescence-based cell-lineage tracing toolsets, employing an inducible method to mark individual cells in Arabidopsis donor somatic tissues at the onset of regeneration. Utilizing these complementary methods, we scrutinized cell identities at the single-cell level and presented compelling evidence that all cells in the regenerated Arabidopsis plants, irrespective of their organ types, originated from a single progenitor cell in the donor somatic tissue. Our discovery suggests a single-cell passage directing the transition from multicellular donor tissue to regenerated plants, thereby creating opportunities for cell-cell competition during plant regeneration-a strategy for maximizing survival.
    Keywords:  DNA barcode; lineage tracing; plant regeneration
    DOI:  https://doi.org/10.1016/j.devcel.2024.10.023
  18. Nat Genet. 2024 Nov 25.
    Split-pool barcoding serves up an epigenomic smorgasbord.
    Vijay Ramani.
      
    DOI:  https://doi.org/10.1038/s41588-024-01980-8
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