Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2011 Jul;39(12):4975-83.
doi: 10.1093/nar/gkr079. Epub 2011 Mar 3.

G4 motifs correlate with promoter-proximal transcriptional pausing in human genes

Johanna Eddy  1 , Aarthy C Vallur, Sudir Varma, Hongfang Liu, William C Reinhold, Yves Pommier, Nancy Maizels
Affiliations

G4 motifs correlate with promoter-proximal transcriptional pausing in human genes

Johanna Eddy et al. Nucleic Acids Res. 2011 Jul.

Abstract

The RNA Pol II transcription complex pauses just downstream of the promoter in a significant fraction of human genes. The local features of genomic structure that contribute to pausing have not been defined. Here, we show that genes that pause are more G-rich within the region flanking the transcription start site (TSS) than RefSeq genes or non-paused genes. We show that enrichment of binding motifs for common transcription factors, such as SP1, may account for G-richness upstream but not downstream of the TSS. We further show that pausing correlates with the presence of a GrIn1 element, an element bearing one or more G4 motifs at the 5'-end of the first intron, on the non-template DNA strand. These results suggest potential roles for dynamic G4 DNA and G4 RNA structures in cis-regulation of pausing, and thus genome-wide regulation of gene expression, in human cells.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Inverse correlation between Pol II binding and G-richness at the TSS. Graph of the frequency Pol II binding sites (1), CpG dinucleotides, and the frequency of G-richness in the interval −1000 to +1000 around the TSS. G-richness was defined as the frequency within each set of genes of 100 nt sequences containing the G4 DNA signature motif, G≥3NxG≥3NxG≥3NxG≥3 (4).
Figure 2.
Figure 2.
G4 motifs are enriched near promoters of paused genes. (A) Graph of the frequency of G-richness in genes defined as paused from the NCI-60 database in the interval −1000 to +1000 around the TSS. (B) Graph of the frequency of G-richness in genes in which Pol II is stably associated with the TSS in the absence of gene expression in the interval −1000 to +1000 around the TSS. This data set derives from analysis of primary resting human CD4+ T cells (1), and corresponds to the same data set for which genome-wide analysis Pol II position is presented in Figure 1. (C) Graph of the frequency of G-richness in the interval −1000 to +1000 around the TSS in genes carrying bivalent chromatin marks H3K4me3 and H3K27me3, as determined by analysis of primary resting human CD4+ T cells (1).
Figure 3.
Figure 3.
Strand-biased G-richness downstream of the TSS at paused genes. Graph of the frequency of G-richness of the non-template (dark lines) and template (pale lines) strands in the interval −1000 to +1000 around the TSS for genes in the NCI-60 database classified as paused (left) or non-paused (center), and RefSeq genes (right).
Figure 4.
Figure 4.
Transcriptional regulatory motifs do not account for G-richness near TSS of paused genes. Graph of the frequency of G-richness of non-template (dark lines) and template (pale lines) strands in the interval −1000 to +1000 around the TSS for paused genes (left), non-paused genes (centre) and all human RefSeq genes (right), with the following motifs masked: (A) SP1 motifs. (B) CpG motifs. (C) CpG, SP1, MAZ, KLF, EKLF, EGR-1 and AP-2 motifs.
Figure 5.
Figure 5.
GrIn1 elements correlate with pausing. (A) Graph of the frequency of non-template strand G-richness within 1 kb downstream of the TSS for paused, non-paused genes and RefSeq genes (top). (B) Graph of the frequency of non-template strand G-richness as in Panel A, but with hnRNP A (UAGGGU/A) and hnRNP H (GGGA) motifs masked. (C) Graph of the frequency of non-template strand G-richness as in Panel B, with CpG motifs, hnRNP A (UAGGGU/A) and hnRNP H (GGGA) motifs masked.
Figure 6.
Figure 6.
Regulation of transcriptional pausing at G4 motifs. Model of dynamic nucleic acid structures that may contribute to pausing upon transcription of a G-rich region. Mechanisms that contribute to pausing may include: (i) G4 DNA formed behind an advancing polymerase may be recognized by factors that promote pausing, (ii) G4 DNA structure formed in a ‘pioneering’ round of transcription may serve as a roadblock during the next round of transcription, (iii) a G4 RNA structure in the nascent transcript may communicate a pause to the transcription complex, as occurs in prokaryotes and (iv) a stable co-transcriptional RNA/DNA hybrid may promote pausing, via signals transmitted through the RNA processing apparatus.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Barski A, Cuddapah S, Cui K, Roh TY, Schones DE, Wang Z, Wei G, Chepelev I, Zhao K. High-resolution profiling of histone methylations in the human genome. Cell. 2007;129:823–837. - PubMed
    1. Margaritis T, Holstege FC. Poised RNA polymerase II gives pause for thought. Cell. 2008;133:581–584. - PubMed
    1. Gilmour DS. Promoter proximal pausing on genes in metazoans. Chromosoma. 2009;118:1–10. - PubMed
    1. Eddy J, Maizels N. Conserved elements with potential to form polymorphic G-quadruplex structures in the first intron of human genes. Nucleic Acids Res. 2008;36:1321–1333. - PMC - PubMed
    1. Eddy J, Maizels N. Gene function correlates with potential for G4 DNA formation in the human genome. Nucleic Acids Res. 2006;34:3887–3896. - PMC - PubMed

Publication types