Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo

Jette Bornholdt Lange; Anne Thoustrup Saber; Berit Lilje; Mette Boyd; Mette Jørgensen; Yun Chen; Morana Vitezic; Nicklas Raun Jacobsen; Sarah Søs Poulsen; Trine Berthing; Simon Bressendorff; Kristoffer Vitting-Seerup; Robin Andersson; Karin Sørig Hougaard; Carole L. Yauk; Sabina Halappanavar; Erik Håkan Richard Wallin; Ulla Vogel; Albin Gustav Sandelin

doi:10.1021/acsnano.6b07533

Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo

Jette Bornholdt Lange, Anne Thoustrup Saber, Berit Lilje, Mette Boyd, Mette Jørgensen, Yun Chen, Morana Vitezic, Nicklas Raun Jacobsen, Sarah Søs Poulsen, Trine Berthing, Simon Bressendorff, Kristoffer Vitting-Seerup, Robin Andersson, Karin Sørig Hougaard, Carole L. Yauk, Sabina Halappanavar, Erik Håkan Richard Wallin, Ulla Vogel, Albin Gustav Sandelin

12 Citations (Scopus)

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 language	English
Journal	A C S Nano
Volume	11
Issue number	4
Pages (from-to)	3597-3613
Number of pages	17
ISSN	1936-0851
DOIs	https://doi.org/10.1021/acsnano.6b07533
Publication status	Published - 25 Apr 2017

Keywords

Journal Article

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10.1021/acsnano.6b07533

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Lange, J. B., Saber, A. T., Lilje, B., Boyd, M., Jørgensen, M., Chen, Y., Vitezic, M., Jacobsen, N. R., Poulsen, S. S., Berthing, T., Bressendorff, S., Vitting-Seerup, K., Andersson, R., Hougaard, K. S., Yauk, C. L., Halappanavar, S., Wallin, E. H. R., Vogel, U., & Sandelin, A. G. (2017). Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo. A C S Nano, 11(4), 3597-3613. https://doi.org/10.1021/acsnano.6b07533

Lange, JB, Saber, AT, Lilje, B, Boyd, M, Jørgensen, M, Chen, Y, Vitezic, M, Jacobsen, NR, Poulsen, SS, Berthing, T, Bressendorff, S, Vitting-Seerup, K, Andersson, R, Hougaard, KS, Yauk, CL, Halappanavar, S, Wallin, EHR, Vogel, U & Sandelin, AG 2017, 'Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo', A C S Nano, vol. 11, no. 4, pp. 3597-3613. https://doi.org/10.1021/acsnano.6b07533

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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.",

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doi = "10.1021/acsnano.6b07533",

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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 - 2017/4/25

Y1 - 2017/4/25

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

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DO - 10.1021/acsnano.6b07533

M3 - Journal article

C2 - 28345861

SN - 1936-0851

VL - 11

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EP - 3613

JO - A C S Nano

JF - A C S Nano

IS - 4

ER -

Identification of gene transcription start sites and enhancers responding to pulmonary carbon nanotube exposure in Vivo

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