The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin Structure

Cuesta, Isabel; Zaret, Kenneth S.; Santisteban, Pilar

doi:10.1128/mcb.00758-07

Cited by 71 publications

(54 citation statements)

References 63 publications

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“…A likely explanation is that these TFs act in different cellular contexts or have roles in vivo at these enhancers, such as remodeling chromatin, that are not required for activating transcription in our plasmid-based assay. Consistent with the latter notion, the list includes three Fox family TFs (Foxo4, Foxp3, and Foxd1), which act as pioneer factors that open chromatin during genomic enhancer activation (72)(73)(74), and two NFI TFs (NFIX and NFIC) that interact with histones (75,76) and contribute to remodeling of nucleosome architecture (77,78). The remaining two TFs (Myb and AP-2) have plausible roles in early adipocyte differentiation, regulating the final cell division (79,80) and repressing an alternate cell fate (81), respectively.…”

Section: Elements In the Sequence Flanking Pparγ Motifs Strongly Affectmentioning

confidence: 92%

“…The first class included 11 pairs of inhibitory AP-1/NR pairs that were not tested in the synthetic enhancers. The second class (TFs not required for reporter expression) consisted of two groups: the first group (six pairs) involves synergistic interactions between nuclear receptors and FOX TFs, which have pioneering ability (72)(73)(74); the second group (four pairs) involves interactions between various TFs and AP-2, which may play a role in early adipocyte differentiation by repressing an alternate cell fate (81), but is down-regulated in terminally differentiated adipocytes.…”

Section: Naturally Occurring Enhancers Contain Additional Classes Of mentioning

confidence: 99%

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Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

164

142

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Enhancers regulate gene expression through the binding of sequence-specific transcription factors (TFs) to cognate motifs. Various features influence TF binding and enhancer function-including the chromatin state of the genomic locus, the affinities of the binding site, the activity of the bound TFs, and interactions among TFs. However, the precise nature and relative contributions of these features remain unclear. Here, we used massively parallel reporter assays (MPRAs) involving 32,115 natural and synthetic enhancers, together with high-throughput in vivo binding assays, to systematically dissect the contribution of each of these features to the binding and activity of genomic regulatory elements that contain motifs for PPARγ, a TF that serves as a key regulator of adipogenesis. We show that distinct sets of features govern PPARγ binding vs. enhancer activity. PPARγ binding is largely governed by the affinity of the specific motif site and higher-order features of the larger genomic locus, such as chromatin accessibility. In contrast, the enhancer activity of PPARγ binding sites depends on varying contributions from dozens of TFs in the immediate vicinity, including interactions between combinations of these TFs. Different pairs of motifs follow different interaction rules, including subadditive, additive, and superadditive interactions among specific classes of TFs, with both spatially constrained and flexible grammars. Our results provide a paradigm for the systematic characterization of the genomic features underlying regulatory elements, applicable to the design of synthetic regulatory elements or the interpretation of human genetic variation.gene regulation | transcription factor binding | systems biology

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Section: Elements In the Sequence Flanking Pparγ Motifs Strongly Affectmentioning

confidence: 92%

Section: Naturally Occurring Enhancers Contain Additional Classes Of mentioning

confidence: 99%

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Grossman

Zhang

Wang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

164

142

View full text Add to dashboard Cite

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“…The association was also observed in familial PTC and in patients with radiation-induced PTC (12-15). SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20).…”

mentioning

confidence: 99%

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

Liyanarachchi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The [A] allele of SNP rs965513 in 9q22 has been consistently shown to be highly associated with increased papillary thyroid cancer (PTC) risk with an odds ratio of ∼1.8 as determined by genome-wide association studies, yet the molecular mechanisms remain poorly understood. Previously, we noted that the expression of two genes in the region, forkhead box E1 (FOXE1) and PTC susceptibility candidate 2 (PTCSC2), is regulated by rs965513 in unaffected thyroid tissue, but the underlying mechanisms were not elucidated. Here, we finemapped the 9q22 region in PTC and controls and detected an ∼33-kb linkage disequilibrium block (containing the lead SNP rs965513) that significantly associates with PTC risk. Chromatin characteristics and regulatory element signatures in this block disclosed at least three regulatory elements functioning as enhancers. These enhancers harbor at least four SNPs (rs7864322, rs12352658, rs7847449, and rs10759944) that serve as functional variants. The variant genotypes are associated with differential enhancer activities and/or transcription factor binding activities. Using the chromosome conformation capture methodology, long-range looping interactions of these elements with the promoter region shared by FOXE1 and PTCSC2 in a human papillary thyroid carcinoma cell line (KTC-1) and unaffected thyroid tissue were found. Our results suggest that multiple variants coinherited with the lead SNP and located in long-range enhancers are involved in the transcriptional regulation of FOXE1 and PTCSC2 expression. These results explain the mechanism by which the risk allele of rs965513 predisposes to thyroid cancer.thyroid cancer | genetic susceptibility | long-range enhancer | functional variants | SNP rs965513 P apillary thyroid carcinoma (PTC) is the most common form of thyroid cancer, accounting for >80% of all thyroid malignancy. It is estimated that 62,450 individuals in the United States will be diagnosed with thyroid cancer in 2015 (www.cancer. org/Research/CancerFactsFigures/index). Although PTC is clearly influenced by both genetic and environmental factors, genetic predisposition plays a major role as evidenced by case-control studies (1-3).Genome-wide association studies (GWASs) have linked SNP rs965513 in 9q22 to thyroid cancer, mainly PTC. The odds ratio (OR) for this SNP is as high as ∼1.8 (4). The association between rs965513 and thyroid cancer risk has been independently confirmed in different populations (5-11). The association was also observed in familial PTC and in patients with radiation-induced PTC (12-15). SNP rs965513 resides ∼60 kb upstream of forkhead box E1 (FOXE1) (also known as thyroid transcription factor 2), a critical transcription factor (TF) in thyroid development, differentiation, and function (16)(17)(18)(19). It has been repeatedly proposed that FOXE1 is involved in the tumorigenesis of PTC (11,19,20). A DNA variant (rs1867277) in the promoter region of FOXE1 was reported as a functional variant involved in transcriptional regulation of FOXE1 (19). However, these studi...

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“…Other studies suggest that nicotinamide also may utilize pathways of the mammalian forkhead transcription factor family that oversees processes that can involve cell metabolism, hormone modulation, and apoptosis [1,127,128]. The first member of this family was the Drosophila melanogaster gene Fork head.…”

Section: Innovative Strategies For Neurovascular Protection During Dmmentioning

confidence: 99%

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Maiese

2008

Biomedicine & Pharmacotherapy

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SummaryOxidative stress is a principal pathway for the dysfunction and ultimate destruction of cells in the neuronal and vascular systems for several disease entities, non promoting the ravages of oxidative stress to any less of a degree than diabetes mellitus. Diabetes mellitus is increasing in incidence as a result of changes in human behavior that relate to diet and daily exercise and is predicted to affect almost 400 million individuals worldwide in another two decades. Furthermore, both type 1 and type 2 diabetes mellitus can lead to significant disability in the nervous and cardiovascular systems, such as cognitive loss and cardiac insufficiency. As a result, innovative strategies that directly target oxidative stress to preserve neuronal and vascular longevity could offer viable therapeutic options to diabetic patients in addition to more conventional treatments that are designed to control serum glucose levels. Here we discuss the novel application of nicotinamide, Wnt signaling, and erythropoietin that modulate cellular oxidative stress and offer significant promise for the prevention of diabetic complications in the nervous and vascular systems. Essential to this process is the precise focus upon diverse as well as common cellular pathways governed by nicotinamide, Wnt signaling, and erythropoietin to outline not only the potential benefits, but also the challenges and possible detriments of these therapies. In this way, new avenues of investigation can hopefully bypass toxic complications, or at the very least, avoid contraindications that may limit care and offer both safe and robust clinical treatment for patients.

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The Forkhead Factor FoxE1 Binds to the Thyroperoxidase Promoter during Thyroid Cell Differentiation and Modifies Compacted Chromatin Structure

Cited by 71 publications

References 63 publications

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Systematic dissection of genomic features determining transcription factor binding and enhancer function

Multiple functional variants in long-range enhancer elements contribute to the risk of SNP rs965513 in thyroid cancer

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

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