bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024‒04‒28
four papers selected by
Xiao Qin, University of Oxford
  1. Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer.
  2. Annotating cell types in single-cell ATAC data via the guidance of the underlying DNA sequences.
  3. A logic-incorporated gene regulatory network deciphers principles in cell fate decisions.
  4. Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection.
  1. Cancer Res. 2024 Apr 24.
    Single-Cell and Spatial Transcriptome Profiling Identifies the Transcription Factor BHLHE40 as a Driver of EMT in Metastatic Colorectal Cancer.
    Sheng Yang, Dongsheng Zhang, Qingyang Sun, Hongxu Nie, Yue Zhang, Xiaowei Wang, Yuanjian Huang, Yueming Sun.
      Colorectal cancer (CRC) is one of the most common malignant tumors in humans, with liver metastasis being the primary cause of mortality. The epithelial-mesenchymal transition (EMT) process endows cancer cells with enhanced metastatic potential. To elucidate the cellular mechanisms driving EMT in CRC, we analyzed single-cell RNA-sequencing (scRNA-seq) data from 11 non-metastatic primary tumors (TnM) and 11 metastatic primary tumors (TM) from CRC patients. Compared to TnM group, the TM samples showed elevated numbers of malignant epithelial cell and cancer-associated fibroblast (CAF) subsets that displayed enrichments of EMT, angiogenesis, and TGF-β signaling pathways. One specific TM-enriched subgroup of malignant epithelial cells underwent EMT to trans-differentiate into CXCL1+ CAFs that subsequently differentiated into SFRP2+ CAFs, which was validated by spatial transcriptomic and pseudotime trajectory analyses. Furthermore, cell-cell communication analysis identified BHLHE40 as a probable key transcription factor driving EMT that was associated with poor prognosis. Finally, in vitro and in vivo experiments functionally substantiated that BHLHE40 promoted the proliferation, invasion, migration, EMT, and liver metastasis of CRC cells. In summary, this study identified BHLHE40 as a key transcription factor regulating EMT that promotes liver metastasis in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3264
  2. Nat Comput Sci. 2024 Apr;4(4): 261-262
    Annotating cell types in single-cell ATAC data via the guidance of the underlying DNA sequences.
      
    DOI:  https://doi.org/10.1038/s43588-024-00626-3
  3. Elife. 2024 Apr 23. pii: RP88742. [Epub ahead of print]12
    A logic-incorporated gene regulatory network deciphers principles in cell fate decisions.
    Gang Xue, Xiaoyi Zhang, Wanqi Li, Lu Zhang, Zongxu Zhang, Xiaolin Zhou, Di Zhang, Lei Zhang, Zhiyuan Li.
      Organisms utilize gene regulatory networks (GRN) to make fate decisions, but the regulatory mechanisms of transcription factors (TF) in GRNs are exceedingly intricate. A longstanding question in this field is how these tangled interactions synergistically contribute to decision-making procedures. To comprehensively understand the role of regulatory logic in cell fate decisions, we constructed a logic-incorporated GRN model and examined its behavior under two distinct driving forces (noise-driven and signal-driven). Under the noise-driven mode, we distilled the relationship among fate bias, regulatory logic, and noise profile. Under the signal-driven mode, we bridged regulatory logic and progression-accuracy trade-off, and uncovered distinctive trajectories of reprogramming influenced by logic motifs. In differentiation, we characterized a special logic-dependent priming stage by the solution landscape. Finally, we applied our findings to decipher three biological instances: hematopoiesis, embryogenesis, and trans-differentiation. Orthogonal to the classical analysis of expression profile, we harnessed noise patterns to construct the GRN corresponding to fate transition. Our work presents a generalizable framework for top-down fate-decision studies and a practical approach to the taxonomy of cell fate decisions.
    Keywords:  cell dynamics; cell fate decision; computational biology; developmental biology; driving force; gene expression noise; gene regulatory logic; gene regulatory network; human; mouse; systems biology
    DOI:  https://doi.org/10.7554/eLife.88742
  4. bioRxiv. 2024 Apr 18. pii: 2023.05.15.540875. [Epub ahead of print]
    Robust differential expression testing for single-cell CRISPR screens at low multiplicity of infection.
    Timothy Barry, Kaishu Mason, Kathryn Roeder, Eugene Katsevich.
      Single-cell CRISPR screens (perturb-seq) link genetic perturbations to phenotypic changes in individual cells. The most fundamental task in perturb-seq analysis is to test for association between a perturbation and a count outcome, such as gene expression. We conduct the first-ever comprehensive benchmarking study of association testing methods for low multiplicity-of-infection (MOI) perturb-seq data, finding that existing methods produce excess false positives. We conduct an extensive empirical investigation of the data, identifying three core analysis challenges: sparsity, confounding, and model misspecification. Finally, we develop an association testing method - SCEPTRE low-MOI - that resolves these analysis challenges and demonstrates improved calibration and power.
    DOI:  https://doi.org/10.1101/2023.05.15.540875
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