bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2024–12–29
fourteen papers selected by
Xiao Qin, University of Oxford
  1. Going beyond cell clustering and feature aggregation: Is there single cell level information in single-cell ATAC-seq data?
  2. A hitchhiker's guide to single-cell epigenomics: Methods and applications for cancer research.
  3. Mapping the gene space at single-cell resolution with gene signal pattern analysis.
  4. Intestinal organoid co-culture systems: current approaches, challenges, and future directions.
  5. When Should Colon Cancer Screening Begin? The Impact of Early-Onset Colorectal Cancer and the Reality of an Unscreened Older Population.
  6. Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
  7. Current state and future prospects of spatial biology in colorectal cancer.
  8. Rethinking chromatin accessibility: from compaction to dynamic interactions.
  9. Wnt/β-catenin pathway as a link between therapy resistance-driven epithelial-mesenchymal transition and stemness in colorectal cancer.
  10. Atlas-scale single-cell DNA methylation profiling with sciMETv3.
  11. Temporal genomic analysis of homogeneous tumor models reveals key regulators of immune evasion in melanoma.
  12. Development of a National Colorectal Cancer Screening Research Agenda: An Initiative of the Canadian Screening for Colorectal Cancer Research Network (CanSCCRN).
  13. Decoding cancer etiology with cellular reprogramming.
  14. Making CRISPR more deliverable.
  1. bioRxiv. 2024 Dec 09. pii: 2024.12.04.626927. [Epub ahead of print]
    Going beyond cell clustering and feature aggregation: Is there single cell level information in single-cell ATAC-seq data?
    Aaron Wing Cheung Kwok, Heejung Shim, Davis J McCarthy.
      Single-cell Assay for Transposase Accessible Chromatin with sequencing (scATAC-seq) has become a widely used method for investigating chromatin accessibility at single-cell resolution. However, the resulting data is highly sparse with most data entries being zeros. As such, currently available computational methods for scATAC-seq feature a range of transformation procedures to extract meaningful information from the sparse data. Most notably, these transformations can be categorized into: 1) feature aggregation with known biological associations, 2) pseudo-bulking cells of similar biology, and 3) binarisation of count data. These strategies beg the question of whether or not scATAC-seq data actually has usable single-cell and single-region information as intended from the assay. If we can go beyond aggregated features and pooled cells, it opens up the possibility of more complex statistical tasks that require that degree of granularity. To reach the finest possible resolution of single-cell, single-region information there are inevitably many computational challenges to overcome. Here, we review the major data analysis challenges lying between raw data readout and biological discovery, and discuss the limitations of current data analysis approaches. Lastly, we conclude that chromatin accessibility profiling at true single-cell resolution is not yet achieved with current technology, but that it may be achieved with promising developments in optimising the efficiency of scATAC-seq assays.
    DOI:  https://doi.org/10.1101/2024.12.04.626927
  2. Int J Cancer. 2024 Dec 22.
    A hitchhiker's guide to single-cell epigenomics: Methods and applications for cancer research.
    Marta Moreno-Gonzalez, Isabel Sierra, Jop Kind.
      Genetic mutations are well known to influence tumorigenesis, tumor progression, treatment response and relapse, but the role of epigenetic variation in cancer progression is still largely unexplored. The lack of epigenetic understanding in cancer evolution is in part due to the limited availability of methods to examine such a heterogeneous disease. However, in the last decade the development of several single-cell methods to profile diverse chromatin features (chromatin accessibility, histone modifications, DNA methylation, etc.) has propelled the study of cancer epigenomics. In this review, we detail the current landscape of single-omic and multi-omic single-cell methods with a particular focus on the examination of histone modifications. Furthermore, we provide recommendations on both the application of these methods to cancer research and how to perform initial computational analyses. Together, this review serves as a referential framework for incorporating single-cell methods as an important tool for tumor biology.
    Keywords:  cancer; chromatin; histone modifications; single‐cell epigenomics; tumor heterogeneity
    DOI:  https://doi.org/10.1002/ijc.35307
  3. Nat Comput Sci. 2024 Dec;4(12): 955-977
    Mapping the gene space at single-cell resolution with gene signal pattern analysis.
    Aarthi Venkat, Sam Leone, Scott E Youlten, Eric Fagerberg, John Attanasio, Nikhil S Joshi, Michael Perlmutter, Smita Krishnaswamy.
      In single-cell sequencing analysis, several computational methods have been developed to map the cellular state space, but little has been done to map or create embeddings of the gene space. Here we formulate the gene embedding problem, design tasks with simulated single-cell data to evaluate representations, and establish ten relevant baselines. We then present a graph signal processing approach, called gene signal pattern analysis (GSPA), that learns rich gene representations from single-cell data using a dictionary of diffusion wavelets on the cell-cell graph. GSPA enables characterization of genes based on their patterning and localization on the cellular manifold. We motivate and demonstrate the efficacy of GSPA as a framework for diverse biological tasks, such as capturing gene co-expression modules, condition-specific enrichment and perturbation-specific gene-gene interactions. Then we showcase the broad utility of gene representations derived from GSPA, including for cell-cell communication (GSPA-LR), spatial transcriptomics (GSPA-multimodal) and patient response (GSPA-Pt) analysis.
    DOI:  https://doi.org/10.1038/s43588-024-00734-0
  4. Am J Physiol Gastrointest Liver Physiol. 2024 Dec 23.
    Intestinal organoid co-culture systems: current approaches, challenges, and future directions.
    Ghanyah Al-Qadami, Anita Raposo, Chia-Chi Chien, Chenkai Ma, Ilka Priebe, Maryam Hor, Kim Fung.
      The intestinal microenvironment represents a complex and dynamic ecosystem, comprising a diverse range of epithelial and non-epithelial cells, a protective mucus layer, and a diverse community of gut microbiota. Understanding the intricate interplay between these components is essential for uncovering the mechanisms underlying intestinal health and disease. The development of intestinal organoids, 3D mini-intestines that closely mimic the architecture, cellular diversity, and functionality of the intestine, offers a powerful platform for investigating different aspects of intestinal physiology and pathology. However, current intestinal organoid models, mainly adult stem cell-derived organoids, lack the non-epithelial and microbial components of the intestinal microenvironment. As such, several co-culture systems have been developed to co-culture intestinal organoids with other intestinal elements including microbes (bacteria and viruses) and immune, stromal, and neural cells. These co-culture models allow researchers to recreate the complex intestinal environment and study the intricate crosstalk between different components of the intestinal ecosystem under healthy and pathological conditions. Currently, there are several approaches and methodologies to establish intestinal organoid co-cultures, and each approach has its own strengths and limitations. This review discusses the existing methods for co-culturing intestinal organoids with different intestinal elements, focusing on the methodological approaches, strengths and limitations, and future directions.
    Keywords:  Co-culture; Immune cells; Intestinal organoids; Microbes; Stromal cells
    DOI:  https://doi.org/10.1152/ajpgi.00203.2024
  5. Dig Dis Sci. 2024 Dec 26.
    When Should Colon Cancer Screening Begin? The Impact of Early-Onset Colorectal Cancer and the Reality of an Unscreened Older Population.
    Iris Lansdorp-Vogelaar, Linda Rabeneck.
       BACKGROUND: Recent increases in colorectal cancer (CRC) incidence and mortality under age 50 have led the US to recommend starting screening at age 45 years instead of 50. Several other countries are now also reconsidering the age to start CRC screening.
    AIMS: To aid decision makers in making an informed decision about lowering the starting age of CRC screening in their jurisdictions.
    METHODS: In this article, we present the clinical and modeling evidence for the optimal age to start CRC screening and provide a checklist of considerations for decisions on age to start CRC screening.
    RESULTS: Two observational studies showed that detection of advanced neoplasia in those aged 45-49 years undergoing colonoscopy was at least as high as in those aged 50-54 years. One Taiwanese study reported a 22% reduction in CRC incidence and a 39% reduction in CRC mortality from FIT screening in those 40-49 years compared to those 50 years and older. Nine modeling studies concluded that lowering the age to start screening to age 45 was cost-effective. However, lowering the start age can have negative spill-off effects, such as increased wait times for diagnostic colonoscopy for symptomatic individuals and decreased screening participation. In an effort to support decision making and prevent negative spill-off, the National Colorectal Cancer Screening Network in Canada proposed a Worksheet to determine the resource impact of earlier screening initiation.
    CONCLUSIONS: Lowering the age to start CRC screening to 45 years likely leads to a reduction in CRC incidence and mortality but requires additional healthcare resources. Policy makers can use the worksheet to assess the expected increase and assess the feasibility within their jurisdictions.
    Keywords:  Colorectal cancer; Early-onset; Screening
    DOI:  https://doi.org/10.1007/s10620-024-08738-6
  6. bioRxiv. 2024 Dec 10. pii: 2024.12.06.626451. [Epub ahead of print]
    Chemical perturbations impacting histone acetylation govern colorectal cancer differentiation.
    Pornlada Likasitwatanakul, Zhixin Li, Paul Doan, Sandor Spisak, Akhouri Kishore Raghawan, Qi Liu, Priscilla Liow, Sunwoo Lee, David Chen, Pratyusha Bala, Pranshu Sahgal, Daulet Aitymbayev, Jennifer S Thalappillil, Malvina Papanastasiou, William Hawkins, Steven A Carr, Haeseong Park, James M Cleary, Jun Qi, Nilay S Sethi.
      Dysregulated epigenetic programs that restrict differentiation, reactivate fetal genes, and confer phenotypic plasticity are critical to colorectal cancer (CRC) development. By screening a small molecule library targeting epigenetic regulators using our dual reporter system, we found that inhibiting histone deacetylase (HDAC) 1/2 promotes CRC differentiation and anti-tumor activity. Comprehensive biochemical, chemical, and genetic experiments revealed that on-target blockade of the HDAC1/2 catalytic domain mediated the differentiated phenotype. Unbiased profiling of histone posttranslational modifications induced by HDAC1/2 inhibition nominated acetylation of specific histone lysine residues as potential regulators of differentiation. Genome-wide assessment of implicated marks indicated that H3K27ac gains at HDAC1/2-bound regions associated with open chromatin and upregulation of differentiation genes upon HDAC1/2 inhibition. Disrupting H3K27ac by degrading acetyltransferase EP300 rescued HDAC1/2 inhibitor-mediated differentiation of a patient-derived CRC model using single cell RNA-sequencing. Genetic screens revealed that DAPK3 contributes to CRC differentiation induced by HDAC1/2 inhibition. These results highlight the importance of specific chemically targetable histone modifications in governing cancer cell states and epigenetic reprogramming as a therapeutic strategy in CRC.
    BRIEF SUMMARY: HDAC1/2 inhibition promotes colorectal cancer differentiation via gains in H3K27ac, which can be reversed by blocking its acetyltransferase EP300.
    DOI:  https://doi.org/10.1101/2024.12.06.626451
  7. Front Oncol. 2024 ;14 1513821
    Current state and future prospects of spatial biology in colorectal cancer.
    Francisco G Carranza, Fernando C Diaz, Maria Ninova, Enrique Velazquez-Villarreal.
      Over the past century, colorectal cancer (CRC) has become one of the most devastating cancers impacting the human population. To gain a deeper understanding of the molecular mechanisms driving this solid tumor, researchers have increasingly turned their attention to the tumor microenvironment (TME). Spatial transcriptomics and proteomics have emerged as a particularly powerful technology for deciphering the complexity of CRC tumors, given that the TME and its spatial organization are critical determinants of disease progression and treatment response. Spatial transcriptomics enables high-resolution mapping of the whole transcriptome. While spatial proteomics maps protein expression and function across tissue sections. Together, they provide a detailed view of the molecular landscape and cellular interactions within the TME. In this review, we delve into recent advances in spatial biology technologies applied to CRC research, highlighting both the methodologies and the challenges associated with their use, such as the substantial tissue heterogeneity characteristic of CRC. We also discuss the limitations of current approaches and the need for novel computational tools to manage and interpret these complex datasets. To conclude, we emphasize the importance of further developing and integrating spatial transcriptomics into CRC precision medicine strategies to enhance therapeutic targeting and improve patient outcomes.
    Keywords:  bioinformatics; colorectal cancer; genomics; personalized medicine; spatial biology; spatial proteomics; spatial transcriptomics; translational research
    DOI:  https://doi.org/10.3389/fonc.2024.1513821
  8. Curr Opin Genet Dev. 2024 Dec 19. pii: S0959-437X(24)00148-5. [Epub ahead of print]90 102299
    Rethinking chromatin accessibility: from compaction to dynamic interactions.
    Tom Fillot, Davide Mazza.
      The genome is traditionally divided into condensed heterochromatin and open euchromatin. However, recent findings challenge this binary classification and the notion that chromatin condensation solely governs the accessibility of transcription factors (TFs) and, consequently, gene expression. Instead, chromatin accessibility is emerging as a factor-specific property that is influenced by multiple determinants. These include the mobility of the chromatin fiber, the capacity of TFs to engage repeatedly with it through multivalent interactions, and the four-dimensional organization of its surrounding diffusible space. Unraveling the molecular and biophysical principles that render a genomic target truly accessible remains a significant challenge, but innovative methods for locally perturbing chromatin, coupled with microscopy techniques that offer single-molecule sensitivity, provide an exciting experimental playground to test new hypotheses.
    DOI:  https://doi.org/10.1016/j.gde.2024.102299
  9. Cell Biol Int. 2024 Dec 20.
    Wnt/β-catenin pathway as a link between therapy resistance-driven epithelial-mesenchymal transition and stemness in colorectal cancer.
    Murilo Ramos Rocha, Yuri Kelly Castillo-Medina, Bárbara Martins de Lima Coelho, Luidy Lucas Lopes Rios, Jose Andres Morgado-Diaz.
      The high plasticity of cells undergoing epithelial-mesenchymal transition (EMT) promotes increased tumor heterogeneity, and its interaction with tumor-associated stromal cells appears to contribute to developing a stemness phenotype. Cells with these characteristics exhibit increased resistance to chemotherapy and radiotherapy, leading to disease relapse and metastasis. Here, we discuss the activation of the Wnt/β-catenin pathway in promoting EMT and stemness within the context of cellular resistance to these therapies. We discuss whether EMT and cancer stem cells (CSCs) function in conjunction, independently, or if a link is connecting their development. We further propose that this pathway is necessary to establish a connection between these two phenotypes. And suggest that it could hinder the rise of CSCs from treatment-induced EMT cells when inhibited. Understanding this cellular phenomenon might allow the development of new targeted therapies to improve clinical responses, particularly in colorectal cancer.
    Keywords:  Wnt/β‐catenin pathway; epithelial‐mesenchymal transition; stemness; therapy resistance
    DOI:  https://doi.org/10.1002/cbin.12270
  10. Cell Genom. 2024 Dec 17. pii: S2666-979X(24)00355-0. [Epub ahead of print] 100726
    Atlas-scale single-cell DNA methylation profiling with sciMETv3.
    Ruth V Nichols, Lauren E Rylaarsdam, Brendan L O'Connell, Zohar Shipony, Nika Iremadze, Sonia N Acharya, Andrew C Adey.
      Single-cell methods to assess DNA methylation have not achieved the same level of cell throughput per experiment compared to other modalities, with large-scale datasets requiring extensive automation, time, and other resources. Here, we describe sciMETv3, a combinatorial indexing-based technique that enables atlas-scale libraries to be produced in a single experiment. To reduce the sequencing burden, we demonstrate the compatibility of sciMETv3 with capture techniques to enrich regulatory regions, as well as the ability to leverage enzymatic conversion, which can yield higher library diversity. We showcase the throughput of sciMETv3 by producing a >140,000 cell library from human middle frontal gyrus split across four multiplexed individuals using both Illumina and Ultima sequencing instrumentation. Finally, we introduce sciMET+ATAC to enable high-throughput exploration of the interplay between chromatin accessibility and DNA methylation within the same cell.
    Keywords:  DNA methylation; epigenetics; neuroscience; single cell
    DOI:  https://doi.org/10.1016/j.xgen.2024.100726
  11. Cancer Discov. 2024 Nov 20.
    Temporal genomic analysis of homogeneous tumor models reveals key regulators of immune evasion in melanoma.
    Sapir Cohen Shvefel, Joy A Pai, Yingying Cao, Lipika R Pal, Osnat Bartok, Ronen Levy, Marie J Zemanek, Chen Weller, Ella Herzog, Winnie Yao, Kamir J Hiam-Galvez, Kuoyuan Cheng, Yajie Yin, Peter P Du, Colin J Raposo, Nofar Gumpert, Michele Welti, Julia M Martínez Gómez, Federica Sella, Elizabeta Yakubovich, Irit Orr, Shifra Ben-Dor, Roni Oren, Liat Fellus-Alyagor, Ofra Golani, Ori Jacob Brenner, Tomer M Salame, Mirie Zerbib, Inna Goliand, Dean Ranmar, Ilya Savchenko, Nadav Ketrarou, Alejandro A Schaffer, Rony Dahan, Mitchell P Levesque, Eytan Ruppin, Ansuman T Satpathy, Yardena Samuels.
      Low intra-tumor heterogeneity (ITH) correlates with increased patient survival and immunotherapy response. However, even highly homogeneous tumors are variably aggressive, and the immunological factors impacting aggressiveness remain understudied. Here, we analyzed the mechanisms underlying immune escape in murine tumors with low ITH. We used immunophenotyping and single-cell RNA sequencing to compare the temporal growth of in-vivo transplanted, genetically similar rejected vs. non-rejected single-cell clones. Non-rejected clones showed high infiltration of tumor-associated macrophages (TAMs), lower T-cell infiltration, and increased T-cell exhaustion compared to rejected clones. Comparative analysis of rejection-associated gene expression programs, combined with in-vivo CRISPR knockout screens of candidate regulators, identified Mif (macrophage migration inhibitory factor) as a major contributor to immune rejection. Mif knockout resulted in smaller tumors and reduced TAM infiltration. These results were validated in melanoma patient data. Overall, our homogeneous tumor system can uncover factors regulating growth variability and identifies Mif as critical in aggressive melanoma.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-1422
  12. Curr Oncol. 2024 Dec 18. 31(12): 8010-8022
    Development of a National Colorectal Cancer Screening Research Agenda: An Initiative of the Canadian Screening for Colorectal Cancer Research Network (CanSCCRN).
    Cynthia Kendell, Robin Urquhart, Akua Kyei, Steven J Heitman, Jill Tinmouth.
      The Canadian Screening for Colorectal Cancer Research Network (CanSCCRN) recently set out to develop a national CRC screening research agenda and identify priority research areas. The specific objectives were to (1) identify evidence gaps relevant to CRC screening and the barriers and facilitators to evidence generation and uptake by CRC screening programs, (2) establish high-priority collaborative research ideas to inform best CRC screening practices, and (3) identify one to two research topics for grant development and submission within 12 to 18 months. Three focus groups were conducted with network members and relevant parties (n = 15) to identify evidence gaps, barriers, and facilitators to evidence generation and uptake. Three workshops were subsequently held to discuss focus group findings and develop an action plan for research. An electronic survey was used to prioritize the evidence gaps to be addressed. Overall, five categories of barriers and six categories of facilitators to evidence uptake and generation were identified, as well as 23 evidence gaps to be addressed. Screening participation, post-polypectomy surveillance, and screening age range were identified as research priority research areas. Adequate resourcing and infrastructure, as well as partnerships with knowledge end users, are integral to addressing these research areas and advancing CRC screening programs in Canada and beyond.
    Keywords:  cancer screening; cancer surveillance; colorectal cancer
    DOI:  https://doi.org/10.3390/curroncol31120591
  13. Curr Opin Genet Dev. 2024 Dec 24. pii: S0959-437X(24)00150-3. [Epub ahead of print]90 102301
    Decoding cancer etiology with cellular reprogramming.
    Mo-Fan Huang, Megan E Fisher, Trinh T T Phan, Ruiying Zhao, Dung-Fang Lee.
      Cancer research remains clinically unmet in many areas due to limited access to patient samples and the lack of reliable model systems that truly reflect human cancer biology. The emergence of patient-derived induced pluripotent stem cells and engineered human pluripotent stem cells (hPSCs) has helped overcome these challenges, offering a versatile alternative platform for advancing cancer research. These hPSCs are already proving to be valuable models for studying specific cancer driver mutations, offering insights into cancer origins, pathogenesis, tumor heterogeneity, clonal evolution, and facilitating drug discovery and testing. This article reviews recent progress in utilizing hPSCs for clinically relevant cancer models and highlights efforts to deepen our understanding of fundamental cancer biology.
    DOI:  https://doi.org/10.1016/j.gde.2024.102301
  14. Nat Biomed Eng. 2024 Dec;8(12): 1513
    Making CRISPR more deliverable.
    Filipe V Almeida.
      
    DOI:  https://doi.org/10.1038/s41551-024-01332-1
This page is being maintained by Thomas Krichel. It was last updated on 2025‒01‒05 at 8:11.