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Biochim Biophys Acta. 2016 Nov;1859(11):1411-1428. doi: 10.1016/j.bbagrm.2016.09.002. Epub 2016 Sep 9.

Mechanism of allele specific assembly and disruption of master regulator transcription factor complexes of NF-KBp50, NF-KBp65 and HIF1a on a non-coding FAS SNP.

Author information

1
Department of Paediatric Pneumology, Neonatology and Allergology, Hannover Medical School, Hannover, Germany; Graduate School of Excellence, MD/PhD Programme Molecular Medicine Hannover Biomedical Research School, Hannover Biomedical Research School, Hannover Medical School, Hannover, Germany.
2
Department of Paediatric Pneumology, Neonatology and Allergology, Hannover Medical School, Hannover, Germany.
3
Institute for Human Genetics, Hannover Medical School, Hannover, Germany.
4
Department of Paediatric Pneumology, Neonatology and Allergology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research, Germany.
5
Institute for Biophysical Chemistry, Hannover Medical School, Hannover, Germany.
6
Department of Paediatric Pneumology, Neonatology and Allergology, Hannover Medical School, Hannover, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Centre for Lung Research, Germany. Electronic address: Mekus.Frauke@mh-hannover.de.

Abstract

A challenging question in genetics is to understand the molecular function of non-coding variants of the genome. By using differential EMSA, ChIP and functional genome analysis, we have found that changes in transcription factors (TF) apparent binding affinity and dissociation rates are responsible for allele specific assembly or disruption of master TFs: we observed that NF-KBp50, NF-KBp65 and HIF1a bind with an affinity of up to 10 fold better to the C-allele than to the T-allele of rs7901656 both in vivo and in vitro. Furthermore, we showed that NF-KBp50, p65 and HIF1a form higher order heteromultimeric complexes overlapping rs7901656, implying synergism of action among TFs governing cellular response to infection and hypoxia. With rs7901656 on the FAS gene as a paradigm, we show how allele specific transcription factor complex assembly and disruption by a causal variant contributes to disease and phenotypic diversity. This finding provides the highly needed mechanistic insight into how the molecular etiology of regulatory SNPs can be understood in functional terms.

KEYWORDS:

Allele-specific TF binding; Cystic fibrosis; HIF1a; Higher order multimeric TF complexes; NF-KBp50; NF-KBp65; Non-coding SNP; TF-binding affinity

PMID:
27616356
DOI:
10.1016/j.bbagrm.2016.09.002
[Indexed for MEDLINE]

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