Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor.

Lusska, A; Shen, Emily S.; Whitlock, Jr Jp

doi:10.1016/s0021-9258(18)53289-0

Cited by 147 publications

(36 citation statements)

References 42 publications

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“…Class C proteins also form asymmetric dimer structures upon DNA binding [100,108,115]. This way, ARNT (which has a glutamate at position 9 of the basic domain) binds to CAC half-sites while partnering with AHR (Isoleucine at position 9), HIF-1a (Alanine at position 9) or SIM proteins (Alanine at position 9) for example, that bind to (T/G)NGC, (A/G)C and GT(A/G)C half-sites respectively [64,116]. Furthermore, ARNT changes its flanking sequence preferences depending on the dimerization partners, for example, binding to a GTTCTCAC half-site upon heterodimerizing with AHR and to a CAGCAC when by heterodimerizing with HLF [117].…”

Section: Dimerizationmentioning

confidence: 99%

Mechanisms of Binding Specificity among bHLH Transcription Factors

Martin

Sodaei

Santpere

2021

IJMS

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The transcriptome of every cell is orchestrated by the complex network of interaction between transcription factors (TFs) and their binding sites on DNA. Disruption of this network can result in many forms of organism malfunction but also can be the substrate of positive natural selection. However, understanding the specific determinants of each of these individual TF-DNA interactions is a challenging task as it requires integrating the multiple possible mechanisms by which a given TF ends up interacting with a specific genomic region. These mechanisms include DNA motif preferences, which can be determined by nucleotide sequence but also by DNA’s shape; post-translational modifications of the TF, such as phosphorylation; and dimerization partners and co-factors, which can mediate multiple forms of direct or indirect cooperative binding. Binding can also be affected by epigenetic modifications of putative target regions, including DNA methylation and nucleosome occupancy. In this review, we describe how all these mechanisms have a role and crosstalk in one specific family of TFs, the basic helix-loop-helix (bHLH), with a very conserved DNA binding domain and a similar DNA preferred motif, the E-box. Here, we compile and discuss a rich catalog of strategies used by bHLH to acquire TF-specific genome-wide landscapes of binding sites.

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Section: Dimerizationmentioning

confidence: 99%

Mechanisms of Binding Specificity among bHLH Transcription Factors

Martin

Sodaei

Santpere

2021

IJMS

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“…The consensus sequence for binding the AHR/ARNT dimer is less restrictive and has been identified as 5Ј-CGTG(A/C)(G/C/T)(A/ T)-3Ј. The four core nucleotides of the XRE (5Ј-CGTG-3Ј) are absolutely required for binding, whereas substitutions at other positions reduce binding affinity by up to about 8-fold (10,11). ARNT contacts the thymidine in the 5Ј-CGTG-3Ј core and thus in a region identical to an E-box half site (GTG), whereas AHR binds 5Ј proximal to this in a region differing from the E-box sequence (13).…”

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confidence: 99%

Identification of a Novel Domain in the Aryl Hydrocarbon Receptor Required for DNA Binding

Fukunaga

Hankinson

1996

Journal of Biological Chemistry

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The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that binds DNA in the form of a heterodimer with the AHR nuclear translocator protein (ARNT). Both proteins possess basic helix-loop-helix motifs. ARNT binds to the side of the xenobiotic responsive element (XRE) that resembles an E-box (the sequence recognized by the majority of other basic helix-loop-helix proteins), whereas AHR binds to the side of the XRE that does not conform to the E-box sequence. The basic region of ARNT closely resembles those of other E-box-binding proteins, whereas the "nominal basic region" of AHR (amino acids 27 39), although required for XRE binding, deviates from this consensus. By extensive mutational analysis it is shown here that an additional block of amino acids of AHR (from tyrosine 9 to lysine 20) that contains a highly basic segment is required for XRE binding and transcriptional activation. Deletion of the first nine amino acids negates XRE binding. Substitution of either tyrosine 9 or arginine 14 with alanine eliminates XRE binding, whereas alanine substitutions at certain other sites within the block reduce but do not eliminate binding. The reported absence of the first nine amino acids in the purified protein may therefore be artifactual. These results suggest that the amino acids of AHR involved in binding to the XRE constitute a novel DNA-binding domain, comprising amino acids located within and amino-terminal to the nominal basic region.

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“…These genes demonstrate altered TFBS within their promoter regions and altered transcript abundance in rats, but not the corresponding AHR-ratonized mice. Here we focused on the AHRE-1 (full) motif, because it results in the most productive receptor-DNA interaction (Lusska et al 1993). In particular, three genes were identified that had lost this motif in H/W rats, and demonstrated altered mRNA abundance in only L-E (Sugp1, Rap2c and Armc5).…”

Section: Discussionmentioning

confidence: 99%

Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

Prokopec

Lee

et al. 2019

Arch Toxicol

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The aryl hydrocarbon receptor (AHR) mediates many toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, the AHR alone does not explain the widely different outcomes among organisms. To identify the other factors involved, we evaluated three transgenic mouse lines, each expressing a different rat AHR isoform (rWT, DEL, and INS) providing widely different resistance to TCDD toxicity, as well as C57BL/6 and DBA/2 mice which exhibit a ~ tenfold divergence in TCDD sensitivity (exposures of 5-1000 μg/kg TCDD). We supplement these with whole-genome sequencing, together with transcriptomic and proteomic analyses of the corresponding rat models, Long-Evans (L-E) and Han/Wistar (H/W) rats (having a ~ 1000-fold difference in their TCDD sensitivities; 100 μg/kg TCDD), to identify genes associated with TCDDresponse phenotypes. Overall, we identified up to 50% of genes with altered mRNA abundance following TCDD exposure are associated with a single AHR isoform (33.8%, 11.7%, 5.2% and 0.3% of 3076 genes altered unique to rWT, DEL, C57BL/6 and INS respectively following 1000 μg/kg TCDD). Hepatic Pxdc1 was significantly repressed in all three TCDD-sensitive animal models (C57BL/6 and rWT mice, and L-E rat) after TCDD exposure. Three genes, including Cxxc5, Sugp1 and Hgfac, demonstrated different AHRE-1 (full) motif occurrences within their promoter regions between rat strains, as well as different patterns of mRNA abundance. Several hepatic proteins showed parallel up-or downward alterations with their RNAs, with three genes (SNRK, IGTP and IMPA2) showing consistent, strain-dependent changes. These data show the value of integrating genomic, transcriptomic and proteomic evidence across multi-species models in toxicologic studies.

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Protein-DNA interactions at a dioxin-responsive enhancer. Analysis of six bona fide DNA-binding sites for the liganded Ah receptor.

Cited by 147 publications

References 42 publications

Mechanisms of Binding Specificity among bHLH Transcription Factors

Mechanisms of Binding Specificity among bHLH Transcription Factors

Identification of a Novel Domain in the Aryl Hydrocarbon Receptor Required for DNA Binding

Comparative toxicoproteogenomics of mouse and rat liver identifies TCDD-resistance genes

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