Computational And High-Throughput Approaches For Analyzing Cis-Regulatory Elements

        With the increasing number of eukaryotic genomes available, high-throughput automated tools for identification of regulatory DNA sequences are becoming increasingly feasible. We are developing both a number of computational tools to discover transcriptional regulatory regions, as well as novel high-throughput methods to analyze DNA binding specificities on a global scale. We also continue to investigate the role of sequence-dependent DNA shape in protein-DNA interactions.

 

Current lab members working on this project: Judith Kribelbauer (collaborations with Remo Rohs, Barry Honig and Harmen Bussemaker)

Recent papers:

Quantitative modeling of transcription factor binding specificities using DNA shape. Zhou T, Shen N, Yang L, Abe N, Horton J, et al. Proceedings of the National Academy of Sciences of the United States of America. 2015; 112(15):4654-9.  PMID: 25775564 PMCID: PMC4403198 101.

Deconvolving the recognition of DNA shape from sequence. Abe N, Dror I, Yang L, Slattery M, Zhou T, et al. Cell. 2015; 161(2):307-18.  PMID: 25843630 PMCID: PMC4422406

SELEX-seq: a method for characterizing the complete repertoire of binding site preferences for transcription factor complexes. Riley TR, Slattery M, Abe N, Rastogi C, Liu D, et al. Methods in molecular biology (Clifton, N.J.). 2014; 1196:255-78.  PMID: 25151169 PMCID: PMC4265583

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Examples of DNA structures taken from protein-DNA crystal structures in the Protein Data Base (PDB) showing a wide variety of DNA shapes involved in DNA recognition by proteins (see Rohs et al., 2010).

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Shown is an example of the output of the EDGI tool (http://luna.bioc.columbia.edu/alona/EDGI/). Motifs shared among a set of related Drosophila species are shown by the vertical lines. Clusters of conserved motifs are indicated by the graph in the lower panel. See Sosinsky et. al., (2007) for details.

 

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Relevant links:

EDGI: http://luna.bioc.columbia.edu/alona/EDGI/

TargetExplorer: http://trantor.bioc.columbia.edu/Target_Explorer/

 

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Representative publications:

 

Sosinsky A., Bonin K., Mann R.S., Honig B. (2003) Target Explorer: an automated tool for the identification of new target genes for a specified set of transcription factors. NAR, 31:3589-92.

 

 

Sosinsky, A., Honig, B., Mann, R.S., and Califano, A. Discovering transcriptional regulatory regions in Drosophila by a nonalignment method for phylogenetic footprinting. Proc Natl Acad Sci U S A, 2007. 104(15): p. 6305-10.

PDF: EDGI_PNAS

 

 

Rohs, R., West, S., Sosinsky, A., Liu, P. Mann, RS, and Honig, B. The role of DNA shape in protein-DNA recognition. Nature (article) (2009) 461(7268):1248-53.

 

 

West SM, Rohs R, Mann RS, Honig B.Electrostatic interactions between arginines and the minor groove in the nucleosome. J Biomol Struct Dyn. 2010 Jun;27(6):861-6.

 

 

Rohs, R., Jin, X., West, S. Joshi, R., Honig, B. and Mann, RS. Origins of Specificity in Protein-DNA Recognition. Annual Review of Biochemistry (2010), Volume 79:233-269.

 

 

 

 

The Laboratory of Richard S Mann
Department of Biochemistry and Molecular Biophysics
Columbia University Medical Center
701 West 168th Street, HHSC 1104
New York, NY 10032
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