Identification of Gene Transcription Start Sites and Enhancers Responding to Pulmonary Carbon Nanotube Exposure in Vivo

Jette Bornholdt, Anne Thoustrup Saber, Bait Lilje, Mette Boyd, Mette Juhl Jørgensen, Yun Chen, Morana Vitezic, Nicklas Raun Jacobsen, Sarah Sos Poulsen, Trine Berthing, Simon Bressendorff, Kristoffer Vitting-Seerup, Robin Andersson, Karin Sorig Hougaard, Carole L. Yauk, Sabina Halappanavar, Hakan Wallin, Ulla Birgitte Vogel, Albin Sandelin

    Research output: Contribution to journalJournal articleResearchpeer-review

    Abstract

    Increased use of nanomaterials in industry, medicine, and consumer products has raised concerns over their toxicity. To ensure safe use of nanomaterials, understanding their biological effects at the molecular level is crucial. In particular, the regulatory mechanisms responsible for the cascade of genes activated by nanomaterial exposure are not well-characterized. To this end, we profiled the genome-wide usage of gene transcription start sites and linked active enhancer regions in lungs of C57BL/6 mice 24 h after intratracheal instillation of a single dose of the multiwalled carbon nanotube (MWCNT) Mitsui-7. Our results revealed a massive gene regulatory response, where expression of key inflammatory genes (e.g., Csf3, Il24, and Fgf23) was increased >100-fold 24 h after Mitsui-7 exposure. Many of the Mitsui-7-responsive transcription start sites were alternative transcription start sites for known genes, and the number of alternative transcription start sites used in a given gene was correlated with overall Mitsui-7 response. Strikingly, genes that were up-regulated after Mitsui-7 exposure only through their main annotated transcription start site were linked to inflammatory and defense responses, while genes up-regulated only through alternative transcription start sites were functionally heterogeneous and not inflammation-associated. Furthermore, we identified almost 12 000 active enhancers, many of which were Mitsui-7-responsive, and we identified similarly responding putative target genes. Overall, our study provides the location and activity of Mitsui-7-induced enhancers and transcription start sites, providing a useful resource for targeted experiments elucidating the biological effects of nanomaterials and the identification of biomarkers for early detection of MWCNT-induced inflammation.
    Original languageEnglish
    JournalA C S Nano
    Volume11
    Issue number4
    Pages (from-to)3597-3613
    Number of pages17
    ISSN1936-0851
    DOIs
    Publication statusPublished - 2017

    Keywords

    • Multiwalled carbon nanotubed
    • CAGE
    • TSS
    • Enhancer
    • Inflammation
    • Mitsui-7
    • MWCNT-7

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