Book of Abstracts: Albany 2007

category image Albany 2007
Conversation 15
June 19-23 2007

Telomere-Like Motifs In A Genome Wide Regulatory Role

Comprehensive characterization of all encoded elements is a fundamental prerequisite for understanding biological function. DNA sequence as regulatory elements is well-established; however, DNA structure is relatively unexplored in this context. Using G-quadruplex or G4 DNA (structural motifs commonly found within eukaryote telomores) as a model we researched the role of DNA structure in transcription in both prokaryotes and eurkaryotes.

We first studied 18 representative prokaryotic species. Analyses of over 61,000 ORFs indicated enrichment of G4 motifs in putative regulatory regions. Based on this and several other lines of evidence we predicted that G4 DNA may present regulatory signals and hypothesized regulatory role of G4 DNA during supercoiling stress. Our hypothesis gains support from analysis for 55 DNA-binding proteins in Escherichia coli, which reveals significant (p<0.001) association of G4 motifs with target sites of global regulators FIS, Lrp, and the sigma factor RpoD (σ70), which are believed to be induced by supercoiled DNA (1).

Next we analyzed human, chimpanzee, mouse, and rat genomes (>90,000 promoters). This indicates significant G4 DNA enrichment within proximal promoters and more than 700 promoters were found to conserve at least one G4 motif 'orthologously' across mouse, rat, and human. Genes harboring conserved motifs within putative regulatory regions show significantly enriched expression (z score > 4.0) in more than 75 human tissues. Based on this, we hypothesized wide spread role of G4 DNA in eukaryotic gene regulation. Whole genome expression using microarrays in human cell lines along with real time PCR results support our hypothesis.

We further investigated the molecular mechanism of transcriptional activation mediated by G4 DNA. Expression of the proto-oncogene c-myc was taken as a case study and our results including chromatin immunoprecipitation show the tandem role of G4 motif and a transcription factor in regulation of c-myc. Taken together, this argues for a more wide spread role of G4 DNA than previously appreciated, where G4 DNA could be a candidate regulatory signal.

References and Footnotes
  1. Rawal, P., Kummarasetti, V. B., Ravindran, J., Kumar, N., Halder, K., Sharma, R., Mukerji, M., Das, S. K., Chowdhury, S. Genome Res. 16, 644-655 (2006).

Anjali Verma2
Kangkan Halder2
Pooja Rawal1
Praveen Kumar2
Vinod Yadav1
Rashi Kulshreshta1
Swapan Kumar Das3
Farhan Mohammad4
Abhay Sharma4
Shantanu Chowdhury1,2,*

1G.N.R. Knowledge Centre for Genome Informatics
2Proteomics and Structural Biology Unit
3Functional Genomics Unit
4Comparative Genomics and Gene Expression Unit
Institute of Genomics and Integrative Biology
Mall Road
Delhi 110 007, India

*Phone: 91 11 2766 6157
Fax: 91 11 2766 7471
Email: shantanuc@igib.res.in