bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–05–26
eight papers selected by
Xiao Qin, University of Oxford
  1. Feedback between stochastic gene networks and population dynamics enables cellular decision-making.
  2. A transition tensor for quantifying spatial transcriptome attractors.
  3. Barcoding Notch signaling in the developing brain.
  4. Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer.
  5. Massively parallel in vivo Perturb-seq reveals cell-type-specific transcriptional networks in cortical development.
  6. Acquisition of epithelial plasticity in human chronic liver disease.
  7. Establishing a conceptual framework for holistic cell states and state transitions.
  8. Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs.
  1. Sci Adv. 2024 May 24. 10(21): eadl4895
    Feedback between stochastic gene networks and population dynamics enables cellular decision-making.
    Paul Piho, Philipp Thomas.
      Phenotypic selection occurs when genetically identical cells are subject to different reproductive abilities due to cellular noise. Such noise arises from fluctuations in reactions synthesizing proteins and plays a crucial role in how cells make decisions and respond to stress or drugs. We propose a general stochastic agent-based model for growing populations capturing the feedback between gene expression and cell division dynamics. We devise a finite state projection approach to analyze gene expression and division distributions and infer selection from single-cell data in mother machines and lineage trees. We use the theory to quantify selection in multi-stable gene expression networks and elucidate that the trade-off between phenotypic switching and selection enables robust decision-making essential for synthetic circuits and developmental lineage decisions. Using live-cell data, we demonstrate that combining theory and inference provides quantitative insights into bet-hedging-like response to DNA damage and adaptation during antibiotic exposure in Escherichia coli.
    DOI:  https://doi.org/10.1126/sciadv.adl4895
  2. Nat Methods. 2024 May 22.
    A transition tensor for quantifying spatial transcriptome attractors.
      
    DOI:  https://doi.org/10.1038/s41592-024-02267-w
  3. bioRxiv. 2024 May 10. pii: 2024.05.10.593533. [Epub ahead of print]
    Barcoding Notch signaling in the developing brain.
    Abigail Siniscalco, Roshan Priyarangana Perera, Jessie E Greenslade, Aiden Masters, Hannah Doll, Bushra Raj.
      Developmental signaling inputs are fundamental for shaping cell fates and behavior. However, traditional fluorescent-based signaling reporters have limitations in scalability and molecular resolution of cell types. We present SABER-seq, a CRISPR-Cas molecular recorder that stores transient developmental signaling cues as permanent mutations in cellular genomes for deconstruction at later stages via single-cell transcriptomics. We applied SABER-seq to record Notch signaling in developing zebrafish brains. SABER-seq has two components: a signaling sensor and a barcode recorder. The sensor activates Cas9 in a Notch-dependent manner with inducible control while the recorder accumulates mutations that represent Notch activity in founder cells. We combine SABER-seq with an expanded juvenile brain atlas to define cell types whose fates are determined downstream of Notch signaling. We identified examples wherein Notch signaling may have differential impact on terminal cell fates. SABER-seq is a novel platform for rapid, scalable and high-resolution mapping of signaling activity during development.
    DOI:  https://doi.org/10.1101/2024.05.10.593533
  4. Nat Commun. 2024 May 21. 15(1): 4342
    Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer.
    Jonas Langerud, Ina A Eilertsen, Seyed H Moosavi, Solveig M K Klokkerud, Henrik M Reims, Ingeborg F Backe, Merete Hektoen, Ole H Sjo, Marine Jeanmougin, Sabine Tejpar, Arild Nesbakken, Ragnhild A Lothe, Anita Sveen.
      Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.
    DOI:  https://doi.org/10.1038/s41467-024-48706-2
  5. Cell. 2024 May 14. pii: S0092-8674(24)00476-8. [Epub ahead of print]
    Massively parallel in vivo Perturb-seq reveals cell-type-specific transcriptional networks in cortical development.
    Xinhe Zheng, Boli Wu, Yuejia Liu, Sean K Simmons, Kwanho Kim, Grace S Clarke, Abdullah Ashiq, Joshua Park, Jiwen Li, Zhilin Wang, Liqi Tong, Qizhao Wang, Keerthi T Rajamani, Rodrigo Muñoz-Castañeda, Shang Mu, Tianbo Qi, Yunxiao Zhang, Zi Chao Ngiam, Naoto Ohte, Carina Hanashima, Zhuhao Wu, Xiangmin Xu, Joshua Z Levin, Xin Jin.
      Leveraging AAVs' versatile tropism and labeling capacity, we expanded the scale of in vivo CRISPR screening with single-cell transcriptomic phenotyping across embryonic to adult brains and peripheral nervous systems. Through extensive tests of 86 vectors across AAV serotypes combined with a transposon system, we substantially amplified labeling efficacy and accelerated in vivo gene delivery from weeks to days. Our proof-of-principle in utero screen identified the pleiotropic effects of Foxg1, highlighting its tight regulation of distinct networks essential for cell fate specification of Layer 6 corticothalamic neurons. Notably, our platform can label >6% of cerebral cells, surpassing the current state-of-the-art efficacy at <0.1% by lentivirus, to achieve analysis of over 30,000 cells in one experiment and enable massively parallel in vivo Perturb-seq. Compatible with various phenotypic measurements (single-cell or spatial multi-omics), it presents a flexible approach to interrogate gene function across cell types in vivo, translating gene variants to their causal function.
    Keywords:  AAV vectors; CRISPR screen; brain development; corticogenesis; in vivo Perturb-seq; single cell genomics
    DOI:  https://doi.org/10.1016/j.cell.2024.04.050
  6. Nature. 2024 May 22.
    Acquisition of epithelial plasticity in human chronic liver disease.
    Christopher Gribben, Vasileios Galanakis, Alexander Calderwood, Eleanor C Williams, Ruben Chazarra-Gil, Miguel Larraz, Carla Frau, Tobias Puengel, Adrien Guillot, Foad J Rouhani, Krishnaa Mahbubani, Edmund Godfrey, Susan E Davies, Emmanouil Athanasiadis, Kourosh Saeb-Parsy, Frank Tacke, Michael Allison, Irina Mohorianu, Ludovic Vallier.
      For many adult human organs, tissue regeneration during chronic disease remains a controversial subject. Regenerative processes are easily observed in animal models, and their underlying mechanisms are becoming well characterized1-4, but technical challenges and ethical aspects are limiting the validation of these results in humans. We decided to address this difficulty with respect to the liver. This organ displays the remarkable ability to regenerate after acute injury, although liver regeneration in the context of recurring injury remains to be fully demonstrated. Here we performed single-nucleus RNA sequencing (snRNA-seq) on 47 liver biopsies from patients with different stages of metabolic dysfunction-associated steatotic liver disease to establish a cellular map of the liver during disease progression. We then combined these single-cell-level data with advanced 3D imaging to reveal profound changes in the liver architecture. Hepatocytes lose their zonation and considerable reorganization of the biliary tree takes place. More importantly, our study uncovers transdifferentiation events that occur between hepatocytes and cholangiocytes without the presence of adult stem cells or developmental progenitor activation. Detailed analyses and functional validations using cholangiocyte organoids confirm the importance of the PI3K-AKT-mTOR pathway in this process, thereby connecting this acquisition of plasticity to insulin signalling. Together, our data indicate that chronic injury creates an environment that induces cellular plasticity in human organs, and understanding the underlying mechanisms of this process could open new therapeutic avenues in the management of chronic diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07465-2
  7. Cell. 2024 May 23. pii: S0092-8674(24)00461-6. [Epub ahead of print]187(11): 2633-2651
    Establishing a conceptual framework for holistic cell states and state transitions.
    Susanne M Rafelski, Julie A Theriot.
      Cell states were traditionally defined by how they looked, where they were located, and what functions they performed. In this post-genomic era, the field is largely focused on a molecular view of cell state. Moving forward, we anticipate that the observables used to define cell states will evolve again as single-cell imaging and analytics are advancing at a breakneck pace via the collection of large-scale, systematic cell image datasets and the application of quantitative image-based data science methods. This is, therefore, a key moment in the arc of cell biological research to develop approaches that integrate the spatiotemporal observables of the physical structure and organization of the cell with molecular observables toward the concept of a holistic cell state. In this perspective, we propose a conceptual framework for holistic cell states and state transitions that is data-driven, practical, and useful to enable integrative analyses and modeling across many data types.
    DOI:  https://doi.org/10.1016/j.cell.2024.04.035
  8. Nat Biomed Eng. 2024 May 22.
    Genome-wide Cas9-mediated screening of essential non-coding regulatory elements via libraries of paired single-guide RNAs.
    Yufeng Li, Minkang Tan, Almira Akkari-Henić, Limin Zhang, Maarten Kip, Shengnan Sun, Jorian J Sepers, Ningning Xu, Yavuz Ariyurek, Susan L Kloet, Richard P Davis, Harald Mikkers, Joshua J Gruber, Michael P Snyder, Xiao Li, Baoxu Pang.
      The functions of non-coding regulatory elements (NCREs), which constitute a major fraction of the human genome, have not been systematically studied. Here we report a method involving libraries of paired single-guide RNAs targeting both ends of an NCRE as a screening system for the Cas9-mediated deletion of thousands of NCREs genome-wide to study their functions in distinct biological contexts. By using K562 and 293T cell lines and human embryonic stem cells, we show that NCREs can have redundant functions, and that many ultra-conserved elements have silencer activity and play essential roles in cell growth and in cellular responses to drugs (notably, the ultra-conserved element PAX6_Tarzan may be critical for heart development, as removing it from human embryonic stem cells led to defects in cardiomyocyte differentiation). The high-throughput screen, which is compatible with single-cell sequencing, may allow for the identification of druggable NCREs.
    DOI:  https://doi.org/10.1038/s41551-024-01204-8
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