USF and NF-E2 Cooperate to Regulate the Recruitment and Activity of RNA Polymerase II in the β-Globin Gene Locus

Zhou, Zhang‐Lin; Li, Xingguo; Deng, Changwang; Ney, Paul A.; Huang, Suming; Bungert, Jörg

doi:10.1074/jbc.m109.098376

Cited by 34 publications

(52 citation statements)

References 70 publications

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“…S6). Other examples of tethered binding include SP1 tethering to HNF4 in HepG2 cells and STAT3 tethering to CEBPB in HeLa cells, both with literature support (Kardassis et al 2002;Zhou et al 2010). Novel predictions of tethering include TCF12 to FOXA and HNF4 in HepG2 cells, IRF1 to NF-Y in K562 cells, SREBF1 to RFX5 in HepG2 cells, and SIX5 to ZNF143 in GM12878 cells (Supplemental Table S3).…”

Section: Analysis Of Sites Of 119 Tfs In the Human Genomementioning

confidence: 91%

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

et al. 2012

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Chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-seq) has become the dominant technique for mapping transcription factor (TF) binding regions genome-wide. We performed an integrative analysis centered around 457 ChIP-seq data sets on 119 human TFs generated by the ENCODE Consortium. We identified highly enriched sequence motifs in most data sets, revealing new motifs and validating known ones. The motif sites (TF binding sites) are highly conserved evolutionarily and show distinct footprints upon DNase I digestion. We frequently detected secondary motifs in addition to the canonical motifs of the TFs, indicating tethered binding and cobinding between multiple TFs. We observed significant position and orientation preferences between many cobinding TFs. Genes specifically expressed in a cell line are often associated with a greater occurrence of nearby TF binding in that cell line. We observed cell-linespecific secondary motifs that mediate the binding of the histone deacetylase HDAC2 and the enhancer-binding protein EP300. TF binding sites are located in GC-rich, nucleosome-depleted, and DNase I sensitive regions, flanked by wellpositioned nucleosomes, and many of these features show cell type specificity. The GC-richness may be beneficial for regulating TF binding because, when unoccupied by a TF, these regions are occupied by nucleosomes in vivo. We present the results of our analysis in a TF-centric web repository Factorbook (http://factorbook.org) and will continually update this repository as more ENCODE data are generated.

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Section: Analysis Of Sites Of 119 Tfs In the Human Genomementioning

confidence: 91%

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

et al. 2012

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“…Previous studies have shown that Pol II interacts with LCR HS2 and with the adult β-globin gene promoter and that the binding increases on induction of MEL cell differentiation (26)(27)(28)(29). As shown in Fig.…”

Section: Resultsmentioning

confidence: 73%

Neutralizing the function of a β-globin–associated cis -regulatory DNA element using an artificial zinc finger DNA-binding domain

Barrow

Masannat

Bungert

2012

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

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Gene expression is primarily regulated by cis-regulatory DNA elements and trans-interacting proteins. Transcription factors bind in a DNA sequence-specific manner and recruit activities that modulate the association and activity of transcription complexes at specific genes. Often, transcription factors belong to families of related proteins that interact with similar DNA sequences. Furthermore, genes are regulated by multiple, sometimes redundant, cis-regulatory elements. Thus, the analysis of the role of a specific DNA regulatory sequence and the interacting proteins in the context of intact cells is challenging. In this study, we designed and functionally characterized an artificial DNA-binding domain that neutralizes the function of a cis-regulatory DNA element associated with adult β-globin gene expression. The zinc finger DNA-binding domain (ZF-DBD), comprising six ZFs, interacted specifically with a CACCC site located 90 bp upstream of the transcription start site (-90 β-ZF-DBD), which is normally occupied by KLF1, a major regulator of adult β-globin gene expression. Stable expression of the -90 β-ZF-DBD in mouse erythroleukemia cells reduced the binding of KLF1 with the β-globin gene, but not with locus control region element HS2, and led to reduced transcription. Transient transgenic embryos expressing the -90 β-ZF-DBD developed normally but revealed reduced expression of the adult β-globin gene. These results demonstrate that artificial DNA-binding proteins lacking effector domains are useful tools for studying and modulating the function of cis-regulatory DNA elements.artificial transcription factor | red cell | gene regulation

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“…35 Furthermore, NF-E2 has been shown to cooperate with USF1 to recruit RNA Pol II and increase expression of globin gene promoters. 36 These findings suggest a mechanism by which the ANK1E core promoter becomes activated in erythroid cells, but silent in other cell types where alternative tissue-specific ANK1 core promoters are active. We propose a model in which the expression of NF-E2 in erythroid cells allows interactions with CTCF that bring the ANK1E 3ЈHS1 enhancer and NF-E2 into juxtaposition with the GATA1-dependent ANK1E promoter.…”

Section: Discussionmentioning

confidence: 80%

A tissue-specific chromatin loop activates the erythroid ankyrin-1 promoter

Yocum

Steiner

Seidel

et al. 2012

Blood

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The human ankyrin-1 gene (ANK1) contains 3 tissue-specific alternative promoters. We have shown previously that the erythroid-specific ankyrin 1 (ANK1E) core promoter contains a 5 DNase I hypersensitive site (HS) with barrier insulator function that prevents gene silencing in vitro and in vivo. Mutations in the ANK1E barrier region lead to decreased ANK1 mRNA levels and hereditary spherocytosis. In this report, we demonstrate a second ANK1E regulatory element located in an adjacent pair of DNase I HS located 5.6 kb 3 of the ANK1E promoter at the 3 boundary of an erythroid-specific DNase Isensitive chromatin domain. The 3 regulatory element exhibits enhancer activity in vitro and in transgenic mice, and it has the histone modifications associated with an enhancer element. One of the ANK1E 3HS contains an NF-E2 binding site that is required for enhancer function. We show that a chromatin loop brings the 3 enhancer and NF-E2 into proximity with the 5 barrier region including the ANK1E core promoter. These observations demonstrate a model for the tissuespecific activation of alternative promoters that may be applicable to the ϳ 30% of mammalian genes with alternative promoters that exhibit distinct expression patterns. (Blood. 2012;120(17):3586-3593) IntroductionHereditary spherocytosis (OMIM 182900) is an inherited hemolytic anemia that affects approximately 1 in 2000 people. [1][2][3] Hereditary spherocytosis takes its name from the spherical-shaped erythrocytes observed on the peripheral blood smear of affected patients. 1 Clinically, hereditary spherocytosis patients present with anemia that can vary from nearly asymptomatic to severe and transfusion-dependent. 1 Other hematologic findings include reticulocytosis, elevated mean corpuscular hemoglobin concentration, and increased erythrocyte osmotic fragility after incubation. 1 The most commonly mutated gene in hereditary spherocytosis is ANK1; this gene encodes a critical component of the erythrocyte membrane skeleton, the ankyrin 1 protein. 1 Less frequent mutations associated with hereditary spherocytosis have been described in the SLC4A1 (band 3), SPTB (␤-spectrin), EPB4.2 (band 4.2), and SPTA (␣-spectrin) genes. 1 Most of these mutations occur in the coding sequence of these genes and lead to functional protein deficiencies. Despite advances in diagnostic DNA sequencing, roughly 50% of hereditary spherocytosis patients do not have a molecular diagnosis. 1 Roughly 30% of mammalian genes have multiple, distinct alternative promoters and first exons, 4 and genes expressed in erythroid cells contain an even higher frequency of alternative promoters and first exons (35%). 5 The human ANK1 gene contains 3 distinct, tissue-specific alternative promoters and first exons that are spliced to a common exon 2 in different cell types. The ANK1B promoter and first exon is expressed exclusively in brain and muscle cells and is located 138 kb upstream of exon 2. The erythroid-specific ANK1E promoter and first exon is located 39 kb upstream of exon 2. The ANK1A promoter and...

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USF and NF-E2 Cooperate to Regulate the Recruitment and Activity of RNA Polymerase II in the β-Globin Gene Locus

Cited by 34 publications

References 70 publications

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

Sequence features and chromatin structure around the genomic regions bound by 119 human transcription factors

Neutralizing the function of a β-globin–associated cis -regulatory DNA element using an artificial zinc finger DNA-binding domain

A tissue-specific chromatin loop activates the erythroid ankyrin-1 promoter

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