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Mult Scler Relat Disord. 2014 Jan;3(1):94-106. doi: 10.1016/j.msard.2013.04.005. Epub 2013 May 23.

Molecular network of ChIP-Seq-based NF-κB p65 target genes involves diverse immune functions relevant to the immunopathogenesis of multiple sclerosis.

Author information

1
Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan. Electronic address: satoj@my-pharm.ac.jp.

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:

ChIP-Seq; GenomeJack; Molecular network; Multiple sclerosis; NF-κB; Next generation sequencing

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