scholarly journals Large-Scale Survey of Cell-Differentiation Programs in a Generative Model Reveals Regeneration as an Epiphenomenon of Development

2019 ◽  
Author(s):  
Somya Mani ◽  
Tsvi Tlusty
Keyword(s):  
Cell Differentiation ◽  
Large Scale ◽  
Asymmetric Cell Division ◽  
Life Forms ◽  
Directed Acyclic Graphs ◽  
Generative Model ◽  
Whole Body ◽  
Cell Type ◽  
Acyclic Graphs ◽  
Large Scale Survey

SummaryDevelopment combines three basic processes — asymmetric cell division, signaling and gene regulation — in a multitude of ways to create an overwhelming diversity of multicellular life-forms. Here, we attempt to chart this diversity using a generative model. We sample millions of biologically feasible developmental schemes, allowing us to comment on the statistical properties of cell-differentiation trajectories they produce. Our results indicate that, in contrast to common views, cell-type lineage graphs are unlikely to be tree-like. Instead, they are more likely to be directed acyclic graphs, with multiple lineages converging on the same terminal cell-type. Additionally, in line with the hypothesis that whole body regeneration is an epiphenomenon of development, a majority of the ‘organisms’ generated by our model can regenerate using pluripotent cells. The generative framework is modular and flexible, and can be adapted to test additional hypotheses about general features of development.

scholarly journals A comprehensive survey of developmental programs reveals a dearth of tree-like lineage graphs and ubiquitous regeneration

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Somya Mani ◽  
Tsvi Tlusty
Keyword(s):  
Asymmetric Cell Division ◽  
Life Forms ◽  
Directed Acyclic Graphs ◽  
Whole Body ◽  
Cell Type ◽  
Pluripotent Cells ◽  
Lineage Differentiation ◽  
Comprehensive Survey ◽  
Organismal Development ◽  
Multicellular Organisms

Abstract Background Multicellular organisms are characterized by a wide diversity of forms and complexity despite a restricted set of key molecules and mechanisms at the base of organismal development. Development combines three basic processes—asymmetric cell division, signaling, and gene regulation—in a multitude of ways to create this overwhelming diversity of multicellular life forms. Here, we use a generative model to test the limits to which such processes can be combined to generate multiple differentiation paths during development, and attempt to chart the diversity of multicellular organisms generated. Results We sample millions of biologically feasible developmental schemes, allowing us to comment on the statistical properties of cell differentiation trajectories they produce. We characterize model-generated “organisms” using the graph topology of their cell type lineage maps. Remarkably, tree-type lineage differentiation maps are the rarest in our data. Additionally, a majority of the “organisms” generated by our model appear to be endowed with the ability to regenerate using pluripotent cells. Conclusions Our results indicate that, in contrast to common views, cell type lineage graphs are unlikely to be tree-like. Instead, they are more likely to be directed acyclic graphs, with multiple lineages converging on the same terminal cell type. Furthermore, the high incidence of pluripotent cells in model-generated organisms stands in line with the long-standing hypothesis that whole body regeneration is an epiphenomenon of development. We discuss experimentally testable predictions of our model and some ways to adapt the generative framework to test additional hypotheses about general features of development.

scholarly journals Learning directed acyclic graphs from large-scale genomics data

2017 ◽  
Vol 2017 (1) ◽  
Author(s):  
Fabio Nikolay ◽  
Marius Pesavento ◽  
George Kritikos ◽  
Nassos Typas
Keyword(s):  
Large Scale ◽  
Directed Acyclic Graphs ◽  
Acyclic Graphs

scholarly journals Occurrence and Molecular Variability of Kiwifruit Viruses in Actinidia deliciosa ‘Xuxiang’ in the Shaanxi Province of China

Plant Disease ◽  
2019 ◽  
Vol 103 (6) ◽  
pp. 1309-1318 ◽  
Author(s):  
Lei Zhao ◽  
Wen Yang ◽  
Yuanle Zhang ◽  
Zhanmin Wu ◽  
Qiao-Chun Wang ◽  
...  
Keyword(s):  
Large Scale ◽  
Primary Source ◽  
Potato Virus X ◽  
Shaanxi Province ◽  
Multiple Infection ◽  
First Report ◽  
Molecular Variability ◽  
Large Scale Survey ◽  
Actinidia Spp ◽  
Main Producer

Kiwifruit (Actinidia spp.) is an economically substantial fruit crop with China the main producer. China is the primary source of wild kiwifruit and the largest producer of kiwifruit in terms of both production and planting area, and Shaanxi province is the largest kiwifruit producer in China. Previous studies reported presence of kiwifruit viruses in Actinidia chinensis. In this study, six viruses were identified in kiwifruit ‘Xuxiang’ (A. deliciosa) in Shaanxi, China. The incidence, distribution, and genetic diversity of these viruses were studied. The results showed that Actinidia virus A (AcVA), Actinidia virus B (AcVB), Actinidia chlorotic ringspot-associated virus (AcCRaV), cucumber mosaic virus (CMV), apple stem grooving virus (ASGV), and potato virus X (PVX) were the main viruses infecting Xuxiang kiwifruit in Shaanxi, China. Incidence of the various viruses with both single and multiple infection varied with different kiwifruit-growing counties. For single virus infection, the highest and the lowest numbers of samples infected were about 22 for AcCRaV and 0 for AcVB in Meixian out of 170 samples, 12 for AcVA and 0 for CMV in Zhouzhi out of 120 samples, 10 for AcVA and 0 for AcVB, AcCRaV, ASGV, PVX, and CMV in Yangling out of 70 samples, and 8 for AcCRaV and CMV and 0 for AcVA, AcVB, ASGV, and PVX in Hanzhong out of 80 samples, respectively. Samples which were multiply infected with two or more viruses were also detected. Analysis of the phylogenetic tree of these viruses showed some genetic variability in the AcVA, AcVB, and AcCRaV isolates of Shaanxi kiwifruit. There was no obvious molecular variation in the coat protein genes of ASGV, CMV, and PVX virus isolates from Shaanxi kiwifruit. The present study is the first large-scale survey of kiwifruit viruses in Shaanxi, China. To our knowledge, this is the first report of PVX infecting kiwifruit and the first report of molecular variability of AcVA, AcVB, and AcCRaV. These results provide important data for studying the genetic evolution of AcVA, AcVB, AcCRaV, ASGV, CMV, and PVX.

scholarly journals Interplay of BAF and MLL4 promotes cell type-specific enhancer activation

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Young-Kwon Park ◽  
Ji-Eun Lee ◽  
Zhijiang Yan ◽  
Kaitlin McKernan ◽  
Tommy O’Haren ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Chromatin Remodeling ◽  
Direct Evidence ◽  
Cell Type ◽  
Chromatin Regulators ◽  
Chromatin Remodeling Complex ◽  
Histone H3k4 ◽  
Cell Type Specific ◽  
Pioneer Transcription Factor ◽  
Factor C

AbstractCell type-specific enhancers are activated by coordinated actions of lineage-determining transcription factors (LDTFs) and chromatin regulators. The SWI/SNF chromatin remodeling complex BAF and the histone H3K4 methyltransferase MLL4 (KMT2D) are both implicated in enhancer activation. However, the interplay between BAF and MLL4 in enhancer activation remains unclear. Using adipogenesis as a model system, we identify BAF as the major SWI/SNF complex that colocalizes with MLL4 and LDTFs on active enhancers and is required for cell differentiation. In contrast, the promoter enriched SWI/SNF complex PBAF is dispensable for adipogenesis. By depleting BAF subunits SMARCA4 (BRG1) and SMARCB1 (SNF5) as well as MLL4 in cells, we show that BAF and MLL4 reciprocally regulate each other’s binding on active enhancers before and during adipogenesis. By focusing on enhancer activation by the adipogenic pioneer transcription factor C/EBPβ without inducing cell differentiation, we provide direct evidence for an interdependent relationship between BAF and MLL4 in activating cell type-specific enhancers. Together, these findings reveal a positive feedback between BAF and MLL4 in promoting LDTF-dependent activation of cell type-specific enhancers.

scholarly journals Correcting Citizens’ Misperceptions about non-Western Immigrants: Corrective Information, Interpretations, and Policy Opinions

2020 ◽  
pp. 1-10 ◽  
Author(s):  
Frederik Juhl Jørgensen ◽  
Mathias Osmundsen
Keyword(s):  
Immigration Policy ◽  
Large Scale ◽  
Total Population ◽  
Survey Experiment ◽  
Correct Information ◽  
The Usa ◽  
Large Scale Survey ◽  
Nationally Representative ◽  
Information Change ◽  
Corrective Information

Abstract Can corrective information change citizens’ misperceptions about immigrants and subsequently lead to favorable immigration opinions? While prior studies from the USA document how corrections about the size of minority populations fail to change citizens’ immigration-related opinions, they do not examine how other facts that speak to immigrants’ cultural or economic dependency rates can influence immigration policy opinions. To extend earlier work, we conducted a large-scale survey experiment fielded to a nationally representative sample of Danes. We randomly expose participants to information about non-Western immigrants’ (1) welfare dependency rate, (2) crime rate, and (3) proportion of the total population. We find that participants update their factual beliefs in light of correct information, but reinterpret the information in a highly selective fashion, ultimately failing to change their policy preferences.

scholarly journals STEM-20. A CANCER STEM CELL-SELECTIVE APOPTOSIS-INDUCING SMALL MOLECULE FOR THE TREATMENT OF GBM

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii200-ii200
Author(s):  
Stephen Skirboll ◽  
Natasha Lucki ◽  
Genaro Villa ◽  
Naja Vergani ◽  
Michael Bollong ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Small Molecules ◽  
Small Molecule ◽  
Large Scale ◽  
Critical Role ◽  
Tumor Formation ◽  
Cell Type ◽  
Caspase 1 ◽  
Activation Assay

Abstract INTRODUCTION Glioblastoma multiforme (GBM) is the most aggressive form of primary brain cancer. A subpopulation of multipotent cells termed GBM cancer stem cells (CSCs) play a critical role in tumor initiation and maintenance, drug resistance, and recurrence following surgery. New therapeutic strategies for the treatment of GBM have recently focused on targeting CSCs. Here we have used an unbiased large-scale screening approach to identify drug-like small molecules that induce apoptosis in GBM CSCs in a cell type-selective manner. METHODS A luciferase-based survival assay of patient-derived GBM CSC lines was established to perform a large-scale screen of ∼one million drug-like small molecules with the goal of identifying novel compounds that are selectively toxic to chemoresistant GBM CSCs. Compounds found to kill GBM CSC lines as compared to control cell types were further characterized. A caspase activation assay was used to evaluate the mechanism of induced cell death. A xenograft animal model using patient-derived GBM CSCs was employed to test the leading candidate for suppression of in vivo tumor formation. RESULTS We identified a small molecule, termed RIPGBM, from the cell-based chemical screen that induces apoptosis in primary patient-derived GBM CSC cultures. The cell type-dependent selectivity of RIPGBM appears to arise at least in part from redox-dependent formation of a proapoptotic derivative, termed cRIPGBM, in GBM CSCs. cRIPGBM induces caspase 1-dependent apoptosis by binding to receptor-interacting protein kinase 2 (RIPK2) and acting as a molecular switch, which reduces the formation of a prosurvival RIPK2/TAK1 complex and increases the formation of a proapoptotic RIPK2/caspase 1 complex. In an intracranial GBM xenograft mouse model, RIPGBM was found to significantly suppress tumor formation. CONCLUSIONS Our chemical genetics-based approach has identified a small molecule drug candidate and a potential drug target that selectively targets cancer stem cells and provides an approach for the treatment of GBMs.

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