title: Transcription factor Dlx3 induces aryl hydrocarbon receptor promoter activity.
abstract: The Distal-less (Dlx) homeobox transcription factors (TFs) play a prominent role in regulating multiple facets of vertebrate biology. Though widely studied as mediators of tissue development, recent work has uncovered a role for this TF family in modulating the vertebrate hematopoietic compartment. Pertinent to our study, murineDlx1-3are expressed in an innate lymphocyte population known as natural killer (NK) cells, and they are implicated to assume a functional role in the NK cell maturation pathway. However, Dlx target genes are poorly understood. InDrosophila, the invertebrateDlxorthologDistal-less(Dll) regulates another transcription factor calledSpineless(ss), which is critical for specifying distal antennal segments. Importantly, the vertebrate ortholog ofssis the aryl hydrocarbon receptor (AhR), a transcription factor recently shown to be important in the regulation of a number of immune cell subsets, including NK cells. Given these findings, we investigated whether Dlx TF family members might analogously regulateAhRin an NK cell context. Our results demonstrate thatDlx3is constitutively co-expressed withAhRin murine and human CD127+NK cells. Critically, we show that Dlx3 inducesAhRpromoter activity by binding to a regulatory region that resides ~5.5 kb upstream of the transcriptional start site. This mechanism is functionally relevant, asDlx3expression in human NK cells significantly enhances TF activity at AhR DNA-binding elements (Xenobiotic Responsive Elements, XREs). Thus, our study defines Dlx3 as a positive regulator of the aryl hydrocarbon receptor.
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.
authors: June Ho
authors: JH
authors: Shin
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.
authors: Mikel D
authors: MD
authors: Haggadone
authors: Division of Head and Neck Surgery, Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA 94305, USA; Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford CA 94305, USA.
authors: John B
authors: JB
authors: Sunwoo
keywords: Aryl hydrocarbon receptor; Dlx3; Natural killer cells; Transcriptional regulation; Xenobiotic response element