bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–05–05
seven papers selected by
Xiao Qin, University of Oxford
  1. Signaling, cancer cell plasticity, and intratumor heterogeneity.
  2. Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
  3. Using single-cell transcriptomics to predict which tumors will respond to targeted therapy.
  4. Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma.
  5. Scalable, Cost-Effective, and Decentralized DNA Barcoding with Oxford Nanopore Sequencing.
  6. Engineering pluripotent stem cells with synthetic biology for regenerative medicine.
  7. Chromatin accessibility during human first-trimester neurodevelopment.
  1. Cell Commun Signal. 2024 May 03. 22(1): 255
    Signaling, cancer cell plasticity, and intratumor heterogeneity.
    Marco Cordani, Ilaria Dando, Giulia Ambrosini, Pedro González-Menéndez.
      Cancer's complexity is in part due to the presence of intratumor heterogeneity and the dynamic nature of cancer cell plasticity, which create substantial obstacles in effective cancer management. Variability within a tumor arises from the existence of diverse populations of cancer cells, impacting the progression, spread, and resistance to treatments. At the core of this variability is the concept of cellular plasticity - the intrinsic ability of cancer cells to alter their molecular and cellular identity in reaction to environmental and genetic changes. This adaptability is a cornerstone of cancer's persistence and progression, making it a formidable target for treatments. Emerging studies have emphasized the critical role of such plasticity in fostering tumor diversity, which in turn influences the course of the disease and the effectiveness of therapeutic strategies. The transformative nature of cancer involves a network of signal transduction pathways, notably those that drive the epithelial-to-mesenchymal transition and metabolic remodeling, shaping the evolutionary path of cancer cells. Despite advancements, our understanding of the precise molecular machinations and signaling networks driving these changes is still evolving, underscoring the necessity for further research. This editorial presents a series entitled "Signaling Cancer Cell Plasticity and Intratumor Heterogeneity" in Cell Communication and Signaling, dedicated to unraveling these complex processes and proposing new avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1186/s12964-024-01643-5
  2. Cell Rep. 2024 May 02. pii: S2211-1247(24)00498-4. [Epub ahead of print]43(5): 114170
    Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming.
    Jose A Martinez-Sarmiento, Maria Pia Cosma, Melike Lakadamyali.
      During cell fate transitions, cells remodel their transcriptome, chromatin, and epigenome; however, it has been difficult to determine the temporal dynamics and cause-effect relationship between these changes at the single-cell level. Here, we employ the heterokaryon-mediated reprogramming system as a single-cell model to dissect key temporal events during early stages of pluripotency conversion using super-resolution imaging. We reveal that, following heterokaryon formation, the somatic nucleus undergoes global chromatin decompaction and removal of repressive histone modifications H3K9me3 and H3K27me3 without acquisition of active modifications H3K4me3 and H3K9ac. The pluripotency gene OCT4 (POU5F1) shows nascent and mature RNA transcription within the first 24 h after cell fusion without requiring an initial open chromatin configuration at its locus. NANOG, conversely, has significant nascent RNA transcription only at 48 h after cell fusion but, strikingly, exhibits genomic reopening early on. These findings suggest that the temporal relationship between chromatin compaction and gene activation during cellular reprogramming is gene context dependent.
    Keywords:  CP: Molecular biology; CP: Stem cell research; Nanog; Oct4; cellular reprogramming; chromatin; pluripotency; single-molecule FISH; super-resolution microscopy
    DOI:  https://doi.org/10.1016/j.celrep.2024.114170
  3. Nat Cancer. 2024 Apr 29.
    Using single-cell transcriptomics to predict which tumors will respond to targeted therapy.
      
    DOI:  https://doi.org/10.1038/s43018-024-00757-6
  4. Comput Struct Biotechnol J. 2024 Dec;23 1689-1704
    Integration of single-nucleus and exosome RNA sequencing dissected inter-cellular communication and biomarkers in pancreatic ductal adenocarcinoma.
    Rong Tang, Zifeng Zhang, Jin Xu, Wei Wang, Qingcai Meng, Yuan Liu, Qiong Du, Chen Liang, Jie Hua, Bo Zhang, Xianjun Yu, Si Shi.
       Background: Mounting evidence underscores the importance of cell communication within the tumor microenvironment, which is pivotal in tumor proliferation, invasion, and metastasis. Exosomes play a crucial role in cell-to-cell communication. Although single-cell RNA sequencing (scRNA-seq) provides insights into individual cell transcriptional characteristics, it falls short of comprehensively capturing exosome-mediated intercellular communication.
    Method: We analyzed Pancreatic Ductal Adenocarcinoma (PDAC) tissues, separating supernatant and precipitate for exosome purification and single-cell nucleus suspension. We then constructed Single-nucleus RNA sequencing (snRNA-seq) and small RNA-seq libraries from these components. Our bioinformatic analysis integrated these sequences with ligand-receptor analysis and public miRNA data to map the cell communication network.
    Results: We established intercellular communication networks using bioinformatic analysis to track exosome miRNA effects and ligand-receptor pairs. Significantly, hsa-miR-1293 emerged as a prognostic biomarker for pancreatic cancer, linked to immune evasion, increased myeloid-derived suppressor cells, and poorer prognosis. Targeting this miRNA may enhance anti-tumor immunity and improve outcomes.
    Conclusion: Our study offers a novel approach to constructing intercellular communication networks using snRNA-seq and exosome-small RNA sequencing. By integrating miRNA tracing with ligand-receptor analysis, we illuminate the complex interactions in the pancreatic cancer microenvironment, highlighting the pivotal role of miRNAs and identifying potential biomarkers and therapeutic targets.
    Keywords:  Bioinformatics; Exosome; Immune microenvironment; MiRNA; Pancreatic cancer
    DOI:  https://doi.org/10.1016/j.csbj.2024.04.021
  5. Methods Mol Biol. 2024 ;2744 223-238
    Scalable, Cost-Effective, and Decentralized DNA Barcoding with Oxford Nanopore Sequencing.
    Amrita Srivathsan, Rudolf Meier.
      DNA barcodes are useful in biodiversity research, but sequencing barcodes with dye termination methods ("Sanger sequencing") has been so time-consuming and expensive that DNA barcodes are not as widely used as they should be. Fortunately, MinION sequencers from Oxford Nanopore Technologies have recently emerged as a cost-effective and efficient alternative for barcoding. MinION barcodes are now suitable for large-scale species discovery and enable specimen identification when the target species are represented in barcode databases. With a MinION, it is possible to obtain 10,000 barcodes from a single flow cell at a cost of less than 0.10 USD per specimen. Additionally, a Flongle flow cell can be used for small projects requiring up to 300 barcodes (0.50 USD per specimen). We here describe a cost-effective laboratory workflow for obtaining tagged amplicons, preparing ONT libraries, sequencing amplicon pools, and analyzing the MinION reads with the software ONTbarcoder. This workflow has been shown to yield highly accurate barcodes that are 99.99% identical to Sanger barcodes. Overall, we propose that the use of MinION for DNA barcoding is an attractive option for all researchers in need of a cost-effective and efficient solution for large-scale species discovery and specimen identification.
    Keywords:  DNA barcoding; Flongle; Integrative taxonomy; MiniON; ONTbarcoder
    DOI:  https://doi.org/10.1007/978-1-0716-3581-0_14
  6. Med Rev (2021). 2024 Apr;4(2): 90-109
    Engineering pluripotent stem cells with synthetic biology for regenerative medicine.
    Yihuan Mao, Siqi Wang, Jiazhen Yu, Wei Li.
      Pluripotent stem cells (PSCs), characterized by self-renewal and capacity of differentiating into three germ layers, are the programmable building blocks of life. PSC-derived cells and multicellular systems, particularly organoids, exhibit great potential for regenerative medicine. However, this field is still in its infancy, partly due to limited strategies to robustly and precisely control stem cell behaviors, which are tightly regulated by inner gene regulatory networks in response to stimuli from the extracellular environment. Synthetic receptors and genetic circuits are powerful tools to customize the cellular sense-and-response process, suggesting their underlying roles in precise control of cell fate decision and function reconstruction. Herein, we review the progress and challenges needed to be overcome in the fields of PSC-based cell therapy and multicellular system generation, respectively. Furthermore, we summarize several well-established synthetic biology tools and their applications in PSC engineering. Finally, we highlight the challenges and perspectives of harnessing synthetic biology to PSC engineering for regenerative medicine.
    Keywords:  PSC-based cell therapy; multicellular systems; pluripotent stem cell; regenerative medicine; synthetic biology
    DOI:  https://doi.org/10.1515/mr-2023-0050
  7. Nature. 2024 May 01.
    Chromatin accessibility during human first-trimester neurodevelopment.
    Camiel C A Mannens, Lijuan Hu, Peter Lönnerberg, Marijn Schipper, Caleb C Reagor, Xiaofei Li, Xiaoling He, Roger A Barker, Erik Sundström, Danielle Posthuma, Sten Linnarsson.
      The human brain develops through a tightly organized cascade of patterning events, induced by transcription factor expression and changes in chromatin accessibility. Although gene expression across the developing brain has been described at single-cell resolution1, similar atlases of chromatin accessibility have been primarily focused on the forebrain2-4. Here we describe chromatin accessibility and paired gene expression across the entire developing human brain during the first trimester (6-13 weeks after conception). We defined 135 clusters and used multiomic measurements to link candidate cis-regulatory elements to gene expression. The number of accessible regions increased both with age and along neuronal differentiation. Using a convolutional neural network, we identified putative functional transcription factor-binding sites in enhancers characterizing neuronal subtypes. We applied this model to cis-regulatory elements linked to ESRRB to elucidate its activation mechanism in the Purkinje cell lineage. Finally, by linking disease-associated single nucleotide polymorphisms to cis-regulatory elements, we validated putative pathogenic mechanisms in several diseases and identified midbrain-derived GABAergic neurons as being the most vulnerable to major depressive disorder-related mutations. Our findings provide a more detailed view of key gene regulatory mechanisms underlying the emergence of brain cell types during the first trimester and a comprehensive reference for future studies related to human neurodevelopment.
    DOI:  https://doi.org/10.1038/s41586-024-07234-1
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