Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo
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Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo. / Lange, Jette Bornholdt; Saber, Anne Thoustrup; Lilje, Berit; Boyd, Mette; Jørgensen, Mette; Chen, Yun; Vitezic, Morana; Jacobsen, Nicklas Raun; Poulsen, Sarah Søs; Berthing, Trine; Bressendorff, Simon; Vitting-Seerup, Kristoffer; Andersson, Robin; Hougaard, Karin Sørig; Yauk, Carole L.; Halappanavar, Sabina; Wallin, Erik Håkan Richard; Vogel, Ulla; Sandelin, Albin Gustav.
In: A C S Nano, Vol. 11, No. 4, 2017, p. 3597-3613.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo
AU - Lange, Jette Bornholdt
AU - Saber, Anne Thoustrup
AU - Lilje, Berit
AU - Boyd, Mette
AU - Jørgensen, Mette
AU - Chen, Yun
AU - Vitezic, Morana
AU - Jacobsen, Nicklas Raun
AU - Poulsen, Sarah Søs
AU - Berthing, Trine
AU - Bressendorff, Simon
AU - Vitting-Seerup, Kristoffer
AU - Andersson, Robin
AU - Hougaard, Karin Sørig
AU - Yauk, Carole L.
AU - Halappanavar, Sabina
AU - Wallin, Erik Håkan Richard
AU - Vogel, Ulla
AU - Sandelin, Albin Gustav
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Journal Article
U2 - 10.1021/acsnano.6b07533
DO - 10.1021/acsnano.6b07533
M3 - Journal article
C2 - 28345861
VL - 11
SP - 3597
EP - 3613
JO - A C S Nano
JF - A C S Nano
SN - 1936-0851
IS - 4
ER -
ID: 176695009