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Allelic mutations in noncoding genomic sequences construct novel transcription factor binding sites that promote gene overexpression
Author(s) -
Tian Erming,
Børset Magne,
Sawyer Jeffrey R.,
Brede Gaute,
Våtsveen Thea K.,
Hov Håkon,
Waage Anders,
Barlogie Bart,
Shaughnessy John D.,
Epstein Joshua,
Sundan Anders
Publication year - 2015
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.22280
Subject(s) - genetics , gene , transcription factor , biology , dna binding site , construct (python library) , computational biology , promoter , gene expression , computer science , programming language
The growth and survival factor hepatocyte growth factor (HGF) is expressed at high levels in multiple myeloma (MM) cells. We report here that elevated HGF transcription in MM was traced to DNA mutations in the promoter alleles of HGF . Sequence analysis revealed a previously undiscovered single‐nucleotide polymorphism (SNP) and crucial single‐nucleotide variants (SNVs) in the promoters of myeloma cells that produce large amounts of HGF. The allele‐specific mutations functionally reassembled wild‐type sequences into the motifs that affiliate with endogenous transcription factors NFKB (nuclear factor kappa‐B), MZF1 (myeloid zinc finger 1), and NRF‐2 (nuclear factor erythroid 2‐related factor 2). In vitro, a mutant allele that gained novel NFKB–binding sites directly responded to transcriptional signaling induced by tumor necrosis factor alpha (TNFα) to promote high levels of luciferase reporter. Given the recent discovery by genome‐wide sequencing (GWS) of numerous non‐coding mutations in myeloma genomes, our data provide evidence that heterogeneous SNVs in the gene regulatory regions may frequently transform wild‐type alleles into novel transcription factor binding properties to aberrantly interact with dysregulated transcriptional signals in MM and other cancer cells. © 2015 Wiley Periodicals, Inc.