Genome-Wide Mapping of the Binding Sites of Proteins That Interact with DNA

Abstract Single nucleotide variants (SNVs) located in transcriptional regulatory regions can result in gene expression changes that lead to adaptive or detrimental phenotypic outcomes. Here, we predict gain or loss of binding sites for 741 transcription factors (TFs) across the human genome. We calculated ‘gainability’ and ‘disruptability’ scores for each TF that represent the likelihood of binding sites being created or disrupted, respectively. We found that functional cis-eQTL SNVs are more likely to alter TF binding sites than rare SNVs in the human population. In addition, we show that cancer somatic mutations have different effects on TF binding sites from different TF families on a cancer-type basis. Finally, we discuss the relationship between these results and cancer mutational signatures. Altogether, we provide a blueprint to study the impact of SNVs derived from genetic variation or disease association on TF binding to gene regulatory regions.

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AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer

Molecular and Cellular Biology ◽

10.1128/mcb.00799-08 ◽

2008 ◽

Vol 28 (24) ◽

pp. 7487-7503 ◽

Cited By ~ 72

Author(s):

Poornima Bhat-Nakshatri ◽

Guohua Wang ◽

Hitesh Appaiah ◽

Nikhil Luktuke ◽

Jason S. Carroll ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Binding Sites ◽

Transforming Growth Factor ◽

Cell Types ◽

Estrogen Receptor Α ◽

Estrogen Signaling ◽

Primary Tumors ◽

Genome Wide ◽

Extracellular Signal

ABSTRACT Estrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.

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Genome-Wide Identification of Transcription Start Sites, Promoters and Transcription Factor Binding Sites in E. coli

PLoS ONE ◽

10.1371/journal.pone.0007526 ◽

2009 ◽

Vol 4 (10) ◽

pp. e7526 ◽

Cited By ~ 184

Author(s):

Alfredo Mendoza-Vargas ◽

Leticia Olvera ◽

Maricela Olvera ◽

Ricardo Grande ◽

Leticia Vega-Alvarado ◽

...

Keyword(s):

Transcription Factor ◽

Binding Sites ◽

Transcription Factor Binding Sites ◽

Transcription Factor Binding ◽

Transcription Start ◽

Transcription Start Sites ◽

E Coli ◽

Factor Binding ◽

Genome Wide

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Genome-wide analysis of Nkx2.2 binding sites using ChIP-tag sequencing (ChIP-TS)

Developmental Biology ◽

10.1016/j.ydbio.2007.03.226 ◽

2007 ◽

Vol 306 (1) ◽

pp. 354

Author(s):

Brad Hoffman ◽

Daniel Kok ◽

Joy Witzsche ◽

Martin Hirst ◽

Gordon Robertson ◽

...

Keyword(s):

Binding Sites ◽

Genome Wide Analysis ◽

Genome Wide

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Investigation of the Interaction of Human Origin Recognition Complex Subunit 1 with G-Quadruplex DNAs of Human c-myc Promoter and Telomere Regions

International Journal of Molecular Sciences ◽

10.3390/ijms22073481 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3481

Author(s):

Afaf Eladl ◽

Yudai Yamaoki ◽

Shoko Hoshina ◽

Haruka Horinouchi ◽

Keiko Kondo ◽

...

Keyword(s):

Fluorescence Anisotropy ◽

Binding Sites ◽

Replication Origin ◽

Origin Recognition Complex ◽

Chemical Shift Perturbation ◽

Human Origin ◽

Replication Origins ◽

Genome Wide ◽

G Quadruplex ◽

Origin Recognition

Origin recognition complex (ORC) binds to replication origins in eukaryotic DNAs and plays an important role in replication. Although yeast ORC is known to sequence-specifically bind to a replication origin, how human ORC recognizes a replication origin remains unknown. Previous genome-wide studies revealed that guanine (G)-rich sequences, potentially forming G-quadruplex (G4) structures, are present in most replication origins in human cells. We previously suggested that the region comprising residues 413–511 of human ORC subunit 1, hORC1413–511, binds preferentially to G-rich DNAs, which form a G4 structure in the absence of hORC1413–511. Here, we investigated the interaction of hORC1413-511 with various G-rich DNAs derived from human c-myc promoter and telomere regions. Fluorescence anisotropy revealed that hORC1413–511 binds preferentially to DNAs that have G4 structures over ones having double-stranded structures. Importantly, circular dichroism (CD) and nuclear magnetic resonance (NMR) showed that those G-rich DNAs retain the G4 structures even after binding with hORC1413–511. NMR chemical shift perturbation analyses revealed that the external G-tetrad planes of the G4 structures are the primary binding sites for hORC1413–511. The present study suggests that human ORC1 may recognize replication origins through the G4 structure.

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