Direct Conversion of C. elegans Germ Cells into Specific Neuron Types

Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University Medical Center, New York, NY 10032, USA.
Science (Impact Factor: 33.61). 01/2011; 331(6015):304-8. DOI: 10.1126/science.1199082
Source: PubMed

ABSTRACT The ability of transcription factors to directly reprogram the identity of cell types is usually restricted and is defined by cellular context. Through the ectopic expression of single Caenorhabditis elegans transcription factors, we found that the identity of mitotic germ cells can be directly converted into that of specific neuron types: glutamatergic, cholinergic, or GABAergic. This reprogramming event requires the removal of the histone chaperone LIN-53 (RbAp46/48 in humans), a component of several histone remodeling and modifying complexes, and this removal can be mimicked by chemical inhibition of histone deacetylases. Our findings illustrate the ability of germ cells to be directly converted into individual, terminally differentiated neuron types and demonstrate that a specific chromatin factor provides a barrier for cellular reprogramming.

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Available from: Paschalis Kratsios, Aug 18, 2015
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    • "These findings are consistent with the possibility that the ectopic somatic cells induced by ER stress in the tumorous gonad are derived from the germ cells themselves, uncovering ER stress as a potent regulator of germ cell pluripotency. Importantly, unlike previously identified regulators of germ cell pluripotency, all of which act at the final steps of the transdifferentiation process by directly regulating gene expression (Ciosk et al., 2006; Tursun et al., 2011; Patel et al., 2012; Updike et al., 2014); ER stress and ER homeostasis likely act further upstream, linking between cellular and organismal physiology and germ cell fate. ire-1 promotes ER stress-induced germ cell transdifferentiation in the gonad of gld-1-deficient animals independently of xbp-1 "
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    ABSTRACT: Deciphering effective ways to suppress tumor progression and to overcome acquired apoptosis resistance of tumor cells are major challenges in the tumor therapy field. We propose a new concept by which tumor progression can be suppressed by manipulating tumor cell identity. In this study, we examined the effect of ER stress on apoptosis resistant tumorous cells in a Caenorhabditis elegans germline tumor model. We discovered that ER stress suppressed the progression of the lethal germline tumor by activating the ER stress sensor IRE-1. This suppression was associated with the induction of germ cell transdifferentiation into ectopic somatic cells. Strikingly, transdifferentiation of the tumorous germ cells restored their ability to execute apoptosis and enabled their subsequent removal from the gonad. Our results indicate that tumor cell transdifferentiation has the potential to combat cancer and overcome the escape of tumor cells from the cell death machinery.
    eLife Sciences 07/2015; 4:e08005. DOI:10.7554/eLife.08005#.dpuf · 9.32 Impact Factor
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    • "Depictions of transcription networks based on these conventions often show ''master transcription regulators'' and target genes as nodes (balls) and regulatory interactions as edges (lines) between these nodes (Figures 1A and 1B). Although the term master transcription regulator is used in many different ways in the literature (Chan and Kyba, 2013), we define it, for the purpose of this article, as a transcription regulator (1) whose presence is required to carry out the specific biological process controlled by the network and (2) whose ectopic expression alone or in combination with other regulators can trigger the biological process even in the absence of the ordinary developmental or environmental signals (Halder et al., 1995; Takahashi and Yamanaka, 2006; Tapscott et al., 1988; Tursun et al., 2011; Vierbuchen et al., 2010; Zordan et al., 2007). "
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    ABSTRACT: When transcription regulatory networks are compared among distantly related eukaryotes, a number of striking similarities are observed: a larger-than-expected number of genes, extensive overlapping connections, and an apparently high degree of functional redundancy. It is often assumed that the complexity of these networks represents optimized solutions, precisely sculpted by natural selection; their common features are often asserted to be adaptive. Here, we discuss support for an alternative hypothesis: the common structural features of transcription networks arise from evolutionary trajectories of "least resistance"-that is, the relative ease with which certain types of network structures are formed during their evolution. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 05/2015; 161(4):714-723. DOI:10.1016/j.cell.2015.04.014 · 32.24 Impact Factor
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    • "First, fibroblasts were treated with the histone deacetylase (HDAC) inhibitor valproic acid (VPA). VPA is known to enhance reprogramming and transdifferentiation processes (Huangfu et al., 2008; Tursun et al., 2011) and increased the effect of CB on sphere size in our protocol (Figure 2B). VPA treatment was followed by induction of a neural precursor fate by CB treatment in neural stem cell medium. "
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    ABSTRACT: Direct transdifferentiation of somatic cells is a promising approach to obtain patient-specific cells for numerous applications. However, conversion across germ-layer borders often requires ectopic gene expression with unpredictable side effects. Here, we present a gene-free approach that allows efficient conversion of human fibroblasts via a transient progenitor stage into Schwann cells, the major glial cell type of peripheral nerves. Using a multikinase inhibitor, we transdifferentiated fibroblasts into transient neural precursors that were subsequently further differentiated into Schwann cells. The resulting induced Schwann cells (iSCs) expressed numerous Schwann cell-specific proteins and displayed neurosupportive and myelination capacity in vitro. Thus, we established a strategy to obtain mature Schwann cells from human postnatal fibroblasts under chemically defined conditions without the introduction of ectopic genes.
    Stem Cell Reports 09/2014; 3(4). DOI:10.1016/j.stemcr.2014.07.014 · 5.37 Impact Factor
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