Article (Scientific journals)
The Effects of Sequence Variation on Genome-wide NRF2 Binding––New Target Genes and Regulatory SNPs
Kuosmanen, Suvi; Viitala, Sari; Laitinen, Tuomo et al.
2016In Nucleic Acids Research, 44 (4), p. 1760-1775
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Abstract :
[en] Transcription factor binding specificity is crucial for proper target gene regulation. Motif discovery algorithms identify the main features of the binding patterns, but the accuracy on the lower affinity sites is often poor. Nuclear factor E2-related factor 2 (NRF2) is a ubiquitous redox-activated transcription factor having a key protective role against endogenous and exogenous oxidant and electrophile stress. Herein, we decipher the effects of sequence variation on the DNA binding sequence of NRF2, in order to identify both genome-wide bind- ing sites for NRF2 and disease-associated regulatory SNPs (rSNPs) with drastic effects on NRF2 binding. Interactions between NRF2 and DNA were studied using molecular modelling, and NRF2 chromatin immunoprecipitation-sequence datasets together with protein binding microarray measurements were utilized to study binding sequence variation in detail. The binding model thus generated was used to identify genome-wide binding sites for NRF2, and genomic binding sites with rSNPs that have strong effects on NRF2 binding and reside on active regulatory elements in human cells. As a proof of concept, miR-126–3p and -5p were identified as NRF2 target microRNAs, and a rSNP (rs113067944) residing on NRF2 target gene (Ferritin, light polypeptide, FTL) promoter was experimentally verified to decrease NRF2 binding and result in decreased transcriptional activity.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Kuosmanen, Suvi;  A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland > Department of Biotechnology and Molecular Medicine
Viitala, Sari;  University of Eastern Finland > School of Pharmacy
Laitinen, Tuomo;  University of Eastern Finland > School of Pharmacy
Peräkylä, Mikael;  University of Eastern Finland > School of Pharmacy
Pölönen, Petri;  A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland > Department of Biotechnology and Molecular Medicine ; Institute of Biomedicine, School of Medicine, University of Eastern Finland
Kansanen, Emilia;  A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland > Department of Biotechnology and Molecular Medicine
Leinonen, Hanna;  A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland > Department of Biotechnology and Molecular Medicine
Raju, Suresh;  Institute of Biomedicine, School of Medicine, University of Eastern Finland
Wienecke, Anke ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) ; Luxembourg Institute of Health
Närvänen, Ale;  University of Eastern Finland > School of Pharmacy
Poso, Antti;  University of Eastern Finland > School of Pharmacy
Heinäniemi, Merja ;  Institute of Biomedicine, School of Medicine, University of Eastern Finland
Heikkinen, Sami;  Institute of Biomedicine, School of Medicine, University of Eastern Finland
Levonen, Anna-Liisa;  A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland > Department of Biotechnology and Molecular Medicine
More authors (4 more) Less
External co-authors :
yes
Language :
English
Title :
The Effects of Sequence Variation on Genome-wide NRF2 Binding––New Target Genes and Regulatory SNPs
Publication date :
January 2016
Journal title :
Nucleic Acids Research
ISSN :
1362-4962
Publisher :
Oxford University Press, Oxford, United Kingdom
Volume :
44
Issue :
4
Pages :
1760-1775
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 30 March 2016

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