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    Repression of Stress-Induced LINE-1 Expression Protects Cancer Cell Subpopulations from Lethal Drug Exposure.
    Cancer Cell 2017 Aug 3;32(2):221-237.e13. Epub 2017 Aug 3.
    Molecular Oncology, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address:
    Maintenance of phenotypic heterogeneity within cell populations is an evolutionarily conserved mechanism that underlies population survival upon stressful exposures. We show that the genomes of a cancer cell subpopulation that survives treatment with otherwise lethal drugs, the drug-tolerant persisters (DTPs), exhibit a repressed chromatin state characterized by increased methylation of histone H3 lysines 9 and 27 (H3K9 and H3K27). We also show that survival of DTPs is, in part, maintained by regulators of H3K9me3-mediated heterochromatin formation and that the observed increase in H3K9me3 in DTPs is most prominent over long interspersed repeat element 1 (LINE-1). Disruption of the repressive chromatin over LINE-1 elements in DTPs results in DTP ablation, which is partially rescued by reducing LINE-1 expression or function.

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    Krannert Institute of Cardiology and Division of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Krannert Institute of Cardiology and Division of Cardiology, Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Krannert Institute of Cardiology and Division of Cardiology, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:
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    Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC.
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    Cocaine dynamically regulates heterochromatin and repetitive element unsilencing in nucleus accumbens.
    Proc Natl Acad Sci U S A 2011 Feb 7;108(7):3035-40. Epub 2011 Feb 7.
    Fishberg Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA.
    Repeated cocaine exposure induces persistent alterations in genome-wide transcriptional regulatory networks, chromatin remodeling activity and, ultimately, gene expression profiles in the brain's reward circuitry. Virtually all previous investigations have centered on drug-mediated effects occurring throughout active euchromatic regions of the genome, with very little known concerning the impact of cocaine exposure on the regulation and maintenance of heterochromatin in adult brain. Here, we report that cocaine dramatically and dynamically alters heterochromatic histone H3 lysine 9 trimethylation (H3K9me3) in the nucleus accumbens (NAc), a key brain reward region. Read More
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    Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
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