bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–06–23
eight papers selected by
Xiao Qin, University of Oxford
  1. Single-Cell Profiling Reveals the Impact of Genetic Alterations on the Differentiation of Inflammation-Induced Murine Colon Tumors.
  2. Linking enhancers to genes.
  3. Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.
  4. Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.
  5. Gene regulatory networks in disease and ageing.
  6. A molecular and cellular perspective on human brain evolution and tempo.
  7. Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.
  8. Recapitulating the tumor microenvironment in a dish, one cell type at a time.
  1. Cancers (Basel). 2024 May 28. pii: 2040. [Epub ahead of print]16(11):
    Single-Cell Profiling Reveals the Impact of Genetic Alterations on the Differentiation of Inflammation-Induced Murine Colon Tumors.
    Ahmed H Ghobashi, Rosie Lanzloth, Christopher A Ladaika, Ashiq Masood, Heather M O'Hagan.
      Genetic mutations and chronic inflammation of the colon contribute to the development of colorectal cancer (CRC). Using a murine model of inflammation-induced colon tumorigenesis, we determined how genetic mutations alter colon tumor cell differentiation. Inflammation induced by enterotoxigenic Bacteroides fragilis (ETBF) colonization of multiple intestinal neoplasia (MinApcΔ716/+) mice triggers loss of heterozygosity of Apc causing colon tumor formation. Here, we report that the addition of BRAFV600E mutation (BRAFF-V600ELgr5tm1(Cre/ERT2)CleMinApcΔ716/+, BLM) or knocking out Msh2 (Msh2LoxP/LoxPVil1-creMinApcΔ716/+, MSH2KO) in the Min model altered colon tumor differentiation. Using single-cell RNA sequencing, we uncovered the differences between BLM, Min, and MSH2KO tumors at a single-cell resolution. BLM tumors showed an increase in differentiated tumor epithelial cell lineages and a reduction in the tumor stem cell population. Interestingly, the tumor stem cell population of BLM tumors had revival colon stem cell characteristics with low WNT signaling and an increase in RevCSC marker gene expression. In contrast, MSH2KO tumors were characterized by an increased tumor stem cell population that had higher WNT signaling activity compared to Min tumors. Furthermore, overall BLM tumors had higher expression of transcription factors that drive differentiation, such as Cdx2, than Min tumors. Using RNA velocity, we identified additional potential regulators of BLM tumor differentiation such as NDRG1. The role of CDX2 and NDRG1 as putative regulators for BLM tumor cell differentiation was verified using organoids derived from BLM tumors. Our results demonstrate the critical connections between genetic mutations and cell differentiation in inflammation-induced colon tumorigenesis. Understanding such roles will deepen our understanding of inflammation-associated colon cancer.
    Keywords:  BRAF mutation; MSI; WNT signaling; colon tumor differentiation; genetic mutations
    DOI:  https://doi.org/10.3390/cancers16112040
  2. Nat Methods. 2024 Jun;21(6): 929
    Linking enhancers to genes.
    Lin Tang.
      
    DOI:  https://doi.org/10.1038/s41592-024-02313-7
  3. Cell Stem Cell. 2024 Jun 11. pii: S1934-5909(24)00185-1. [Epub ahead of print]
    Integrated single-cell analysis defines the epigenetic basis of castration-resistant prostate luminal cells.
    Jason S Kirk, Jie Wang, Mark Long, Spencer Rosario, Amanda Tracz, Yibing Ji, Rahul Kumar, Xiaozhuo Liu, Anmbreen Jamroze, Prashant K Singh, Igor Puzanov, Gurkamal Chatta, Qing Cheng, Jiaoti Huang, Jeffrey L Wrana, Jonathan Lovell, Han Yu, Song Liu, Michael M Shen, Tao Liu, Dean G Tang.
      Understanding prostate response to castration and androgen receptor signaling inhibitors (ARSI) is critical to improving long-term prostate cancer (PCa) patient survival. Here, we use a multi-omics approach on 229,794 single cells to create a mouse single-cell reference atlas for interpreting mouse prostate biology and castration response. Our reference atlas refines single-cell annotations and provides a chromatin context, which, when coupled with mouse lineage tracing, demonstrates that castration-resistant luminal cells are distinct from the pre-existent urethra-proximal stem/progenitor cells. Molecular pathway analysis and therapeutic studies further implicate AP1 (JUN/FOS), WNT/β-catenin, FOXQ1, NF-κB, and JAK/STAT pathways as major drivers of castration-resistant luminal populations with relevance to human PCa. Our datasets, which can be explored through an interactive portal (https://visportal.roswellpark.org/data/tang/), can aid in developing combination treatments with ARSI for advanced PCa patients.
    Keywords:  AP1; castration resistance; differentiation; epigenetic; plasticity; progenitor cells; prostate; prostate cancer; reprogramming; single-cell analysis
    DOI:  https://doi.org/10.1016/j.stem.2024.05.008
  4. Nat Methods. 2024 Jun 18.
    Quantifying cell-state densities in single-cell phenotypic landscapes using Mellon.
    Dominik J Otto, Cailin Jordan, Brennan Dury, Christine Dien, Manu Setty.
      Cell-state density characterizes the distribution of cells along phenotypic landscapes and is crucial for unraveling the mechanisms that drive diverse biological processes. Here, we present Mellon, an algorithm for estimation of cell-state densities from high-dimensional representations of single-cell data. We demonstrate Mellon's efficacy by dissecting the density landscape of differentiating systems, revealing a consistent pattern of high-density regions corresponding to major cell types intertwined with low-density, rare transitory states. We present evidence implicating enhancer priming and the activation of master regulators in emergence of these transitory states. Mellon offers the flexibility to perform temporal interpolation of time-series data, providing a detailed view of cell-state dynamics during developmental processes. Mellon facilitates density estimation across various single-cell data modalities, scaling linearly with the number of cells. Our work underscores the importance of cell-state density in understanding the differentiation processes, and the potential of Mellon to provide insights into mechanisms guiding biological trajectories.
    DOI:  https://doi.org/10.1038/s41592-024-02302-w
  5. Nat Rev Nephrol. 2024 Jun 12.
    Gene regulatory networks in disease and ageing.
    Paula Unger Avila, Tsimafei Padvitski, Ana Carolina Leote, He Chen, Julio Saez-Rodriguez, Martin Kann, Andreas Beyer.
      The precise control of gene expression is required for the maintenance of cellular homeostasis and proper cellular function, and the declining control of gene expression with age is considered a major contributor to age-associated changes in cellular physiology and disease. The coordination of gene expression can be represented through models of the molecular interactions that govern gene expression levels, so-called gene regulatory networks. Gene regulatory networks can represent interactions that occur through signal transduction, those that involve regulatory transcription factors, or statistical models of gene-gene relationships based on the premise that certain sets of genes tend to be coexpressed across a range of conditions and cell types. Advances in experimental and computational technologies have enabled the inference of these networks on an unprecedented scale and at unprecedented precision. Here, we delineate different types of gene regulatory networks and their cell-biological interpretation. We describe methods for inferring such networks from large-scale, multi-omics datasets and present applications that have aided our understanding of cellular ageing and disease mechanisms.
    DOI:  https://doi.org/10.1038/s41581-024-00849-7
  6. Nature. 2024 Jun;630(8017): 596-608
    A molecular and cellular perspective on human brain evolution and tempo.
    Feline W Lindhout, Fenna M Krienen, Katherine S Pollard, Madeline A Lancaster.
      The evolution of the modern human brain was accompanied by distinct molecular and cellular specializations, which underpin our diverse cognitive abilities but also increase our susceptibility to neurological diseases. These features, some specific to humans and others shared with related species, manifest during different stages of brain development. In this multi-stage process, neural stem cells proliferate to produce a large and diverse progenitor pool, giving rise to excitatory or inhibitory neurons that integrate into circuits during further maturation. This process unfolds over varying time scales across species and has progressively become slower in the human lineage, with differences in tempo correlating with differences in brain size, cell number and diversity, and connectivity. Here we introduce the terms 'bradychrony' and 'tachycrony' to describe slowed and accelerated developmental tempos, respectively. We review how recent technical advances across disciplines, including advanced engineering of in vitro models, functional comparative genetics and high-throughput single-cell profiling, are leading to a deeper understanding of how specializations of the human brain arise during bradychronic neurodevelopment. Emerging insights point to a central role for genetics, gene-regulatory networks, cellular innovations and developmental tempo, which together contribute to the establishment of human specializations during various stages of neurodevelopment and at different points in evolution.
    DOI:  https://doi.org/10.1038/s41586-024-07521-x
  7. Cell Mol Life Sci. 2024 Jun 20. 81(1): 274
    Hidden secrets of the cancer genome: unlocking the impact of non-coding mutations in gene regulatory elements.
    Sandra Iñiguez-Muñoz, Pere Llinàs-Arias, Miquel Ensenyat-Mendez, Andrés F Bedoya-López, Javier I J Orozco, Javier Cortés, Ananya Roy, Karin Forsberg-Nilsson, Maggie L DiNome, Diego M Marzese.
      Discoveries in the field of genomics have revealed that non-coding genomic regions are not merely "junk DNA", but rather comprise critical elements involved in gene expression. These gene regulatory elements (GREs) include enhancers, insulators, silencers, and gene promoters. Notably, new evidence shows how mutations within these regions substantially influence gene expression programs, especially in the context of cancer. Advances in high-throughput sequencing technologies have accelerated the identification of somatic and germline single nucleotide mutations in non-coding genomic regions. This review provides an overview of somatic and germline non-coding single nucleotide alterations affecting transcription factor binding sites in GREs, specifically involved in cancer biology. It also summarizes the technologies available for exploring GREs and the challenges associated with studying and characterizing non-coding single nucleotide mutations. Understanding the role of GRE alterations in cancer is essential for improving diagnostic and prognostic capabilities in the precision medicine era, leading to enhanced patient-centered clinical outcomes.
    Keywords:  Enhancers; Insulators; Promoters; Silencers; Single nucleotide polymorphisms; Single nucleotide variants
    DOI:  https://doi.org/10.1007/s00018-024-05314-z
  8. Cell Rep Methods. 2024 Jun 17. pii: S2667-2375(24)00156-5. [Epub ahead of print]4(6): 100800
    Recapitulating the tumor microenvironment in a dish, one cell type at a time.
    Benjamin N Ostendorf.
      The tumor microenvironment harbors a variety of different cell types that differentially impact tumor biology. In this issue of Cell Reports Methods, Raffo-Romero et al. standardized and optimized 3D tumor organoids to model the interactions between tumor-associated macrophages and tumor cells in vitro.
    Keywords:  CP: cancer biology; CP: stem cell
    DOI:  https://doi.org/10.1016/j.crmeth.2024.100800
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