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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, murine Dlx1-3 are 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. In Drosophila, the invertebrate Dlx ortholog Distal-less (Dll) regulates another transcription factor called Spineless (ss), which is critical for specifying distal antennal segments. Importantly, the vertebrate ortholog of ss is 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 regulate AhR in an NK cell context. Our results demonstrate that Dlx3 is constitutively co-expressed with AhR in murine and human CD127⁺ NK cells. Critically, we show that Dlx3 induces AhR promoter activity by binding to a regulatory region that resides ~5.5 kb upstream of the transcriptional start site. This mechanism is functionally relevant, as Dlx3 expression 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.

SUBMITTER: Shin JH

PROVIDER: S-EPMC5074085 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Fascin is an actin-bundling protein that is absent from most normal epithelia yet is upregulated in multiple forms of human carcinoma, where its expression correlates clinically with a poor prognosis. How fascin-1 transcription is activated in carcinoma cells is largely unknown, although the hypothesis of regulation by beta-catenin signaling has received attention. The question is important because of the clinical significance of fascin expression in human carcinomas. METHODOLOGY/PRINCIPAL FINDINGS: Through comparative genomics we made an unbiased analysis of the DNA sequence of the fascin-1 promoter region from six mammalian species. We identified two regions in which highly conserved motifs are concentrated. Luciferase promoter reporter assays for the human fascin-1 promoter were carried out in fascin-positive and -negative human breast and colon carcinoma cells, and in human dermal fibroblasts that are constitutively fascin-positive. In all fascin-positive cells, the region -219/+114 that contains multiple highly conserved motifs had strong transcriptional activity. The region -2953/-1582 appeared to contain repressor activity. By examining the effects of single or multiple point mutations of conserved motifs within the -219/+114 region on transcriptional reporter activity, we identified for the first time that the conserved CREB and AhR binding motifs are major determinants of transcriptional activity in human colon carcinoma cells. Chromatin immunoprecipitations for CREB, AhR or beta-catenin from extracts from fascin-positive or -negative human colon carcinoma cells identified that CREB and AhR specifically associate with the -219/+114 region of the FSCN1 promoter in fascin-positive colon carcinoma cells. An association of beta-catenin was not specific to fascin-positive cells. CONCLUSION: Upregulation of fascin-1 in aggressive human carcinomas appears to have a multi-factorial basis. The data identify novel roles for CREB and AhR as major, specific regulators of FSCN-1 transcription in human carcinoma cells but do not support the hypothesis that beta-catenin signaling has a central role.

Project description:Research on the aryl hydrocarbon receptor (AHR) has largely focused on variations in toxic outcomes resulting from its activation by halogenated aromatic hydrocarbons. But the AHR also plays key roles in regulating pathways critical for development, and after decades of research the mechanisms underlying physiological regulation by the AHR remain poorly characterized. Previous studies identified several core genes that respond to xenobiotic AHR ligands across a broad range of species and tissues. However, only limited inferences have been made regarding its role in regulating constitutive gene activity, i.e. in the absence of exogenous ligands. To address this, we profiled transcriptomic variations between AHR-active and AHR-less-active animals in the absence of an exogenous agonist across five tissues, three of which came from rats (hypothalamus, white adipose and liver) and two of which came from mice (kidney and liver). Because AHR status alone has been shown sufficient to alter transcriptomic responses, we reason that by contrasting profiles amongst AHR-variant animals, we may elucidate effects of the AHR on constitutive mRNA abundances.We found significantly more overlap in constitutive mRNA abundances amongst tissues within the same species than from tissues between species and identified 13 genes (Agt, Car3, Creg1, Ctsc, E2f6, Enpp1, Gatm, Gstm4, Kcnj8, Me1, Pdk1, Slc35a3, and Sqrdl) that are affected by AHR-status in four of five tissues. One gene, Creg1, was significantly up-regulated in all AHR-less-active animals. We also find greater overlap between tissues at the pathway level than at the gene level, suggesting coherency to the AHR signalling response within these processes. Analysis of regulatory motifs suggests that the AHR mostly mediates transcriptional regulation via direct binding to response elements.These findings, though preliminary, present a platform for further evaluating the role of the AHR in regulation of constitutive mRNA levels and physiologic function.

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Transcription factor Dlx3 induces aryl hydrocarbon receptor promoter activity.

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