Highlights
- •We identified 918 ChIP-Seq NF-κB p65 binding sites on protein-coding genes.
- •The binding sites were accumulated in promoter and intronic regions.
- •Their molecular network was associated with immune functions relevant to MS.
- •They included 10 MS risk genes and 49 MS brain lesion-specific proteins.
Abstract
Background
The transcription factor nuclear factor-kappa B (NF-κB) acts as a central regulator
of immune response, stress response, cell proliferation, and apoptosis. Aberrant regulation
of NF-κB function triggers development of cancers, metabolic diseases, and autoimmune
diseases. We attempted to characterize a global picture of the NF-κB target gene network
relevant to the immunopathogenesis of multiple sclerosis (MS).
Methods
We identified the comprehensive set of 918 NF-κB p65 binding sites on protein-coding
genes from chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) dataset
of TNFα-stimulated human B lymphoblastoid cells. The molecular network was studied
by a battery of pathway analysis tools of bioinformatics.
Results
The GenomeJack genome viewer showed that NF-κB p65 binding sites were accumulated
in promoter (35.5%) and intronic (54.9%) regions with an existence of the NF-κB consensus
sequence motif. A set of 52 genes (5.7%) corresponded to known NF-κB targets by database
search. KEGG, PANTHER, and Ingenuity Pathways Analysis (IPA) revealed that the NF-κB
p65 target gene network is linked to regulation of immune functions and oncogenesis,
including B cell receptor signaling, T cell activation pathway, Toll-like receptor
signaling, and apoptosis signaling, and molecular mechanisms of cancers. KeyMolnet
indicated an involvement of the complex crosstalk among core transcription factors
in the NF-κB p65 target gene network. Furthermore, the set of NF-κB p65 target genes
included 10 genes among 98 MS risk alleles and 49 molecules among 709 MS brain lesion-specific
proteins.
Conclusions
These results suggest that aberrant regulation of NF-κB-mediated gene expression,
by inducing dysfunction of diverse immune functions, is closely associated with development
and progression of MS.
Keywords
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Article info
Publication history
Published online: May 28, 2013
Accepted:
April 30,
2013
Received in revised form:
April 24,
2013
Received:
December 18,
2012
Identification
Copyright
© 2013 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
