Research


researchGenome analysis views DNA as a linear string of the letters A, C, G, and T but proteins recognize DNA as a three-dimensional object (Figure). Our main interest is to understand better how transcription factors (TFs) recognize nuances in intrinsic DNA structure and to identify TF families for which the readout of local DNA shape contributes to binding specificity and explains distinct functions of closely related TFs. Until recently, our research mainly focused on the analysis of TF binding sites (TFBSs) for which structural information was available. However, sequence information for whole genomes has become available in recent years due to advances in high-throughput sequencing technologies, whereas structural information on that scale is not available. It is still unknown why certain TFs bind to similar DNA sequences but execute different in vivo functions, or in turn bind to diverse sequences. Our scientific contributions suggest that direct chemical contacts with base pairs cannot sufficiently explain binding specificity and that DNA shape is a crucial specificity determinant:

1. We discovered that Drosophila Hox proteins achieve binding specificity through readout of minor groove geometry and that base-specific hydrogen bonds in the major groove are not sufficient for in vivo function (Joshi et al., Cell 2007).

2. Based on the analysis of all available crystal structures of protein-DNA complexes, we generalized our finding that many TF families use arginine residues to recognize minor groove shape and electrostatic potential and that similar shape-dependent interactions with histones contribute to the stabilization of nucleosomes (Rohs et al., Nature 2009).

3. For binding sites of the tumor suppressor p53, we found a different mechanism for altering minor groove shape due to a flip of several base pairs from Watson-Crick to Hoogsteen geometry (Kitayner et al., Nat. Struct. Mol. Biol. 2010).

4. The discovery of minor groove shape recognition has led to a new classification of protein-DNA readout modes in base readout and shape readout (Rohs et al., Annu. Rev. Biochem. 2010), which has already been adopted in a textbook.

5. We developed a high-throughput method for minor groove geometry prediction. In a proof-of-principle study, we published the first application of this approach based on the shape analysis of several hundreds of thousands of TFBSs (Slattery et al., Cell 2011). We predicted the minor groove width of Drosophila Hox binding sites derived from SELEX-seq experiments and discovered that Hox TFs, although they bind to target sites that are similar in sequence, prefer distinct minor groove topographies. Hox TFs responsible for the development of anterior regions of the fly select one shape class while Hox proteins involved in posterior development prefer a different shape class.

6. We are currently expanding our high-throughput method to predict all essential structural features of TFBSs at single nucleotide resolution. This approach is based on the data mining of thousands of Monte Carlo trajectories, which we validated based on all available crystal structures. Using a sliding pentamer window, we derive average conformations at the center of each unique pentamer to predict structural features. Our high-throughput method is very fast in comparison to molecular simulations and predicts shape features of, for instance, the entire yeast genome in about one minute on a single processor. This advance makes DNA shape analysis for the first time expedient on a genome-wide scale.

Building on this high-throughput method for DNA shape prediction, our lab is now working on expanding this approach and will apply DNA shape analysis to a variety of biological questions, which we believe will benefit from integrating studies of DNA sequence and shape. Our immediate research plans are focused on analyzing the role of various intrinsic DNA shape features on a genome-wide basis in achieving DNA binding specificity of closely related TFs. Based on our preliminary results, we expect that genome-wide DNA shape analysis will become an important aspect in interpreting high-throughput sequencing data and provide a better understanding of the genome and its diverse functions.

 



 

April 20, 2017
We published our interactive tool for structural analysis of protein-DNA complexes in NAR. Congrats, Jared!

March 20, 2017
Tsu-Pei was awarded the prestigious Manning Endowed Fellowship. Congrats, Tsu-Pei!

March 20, 2017
Beibei was awarded a competitive Research Enhancement Fellowship. Congrats, Beibei!

February 6, 2017
Our new Mol. Syst. Biol. paper provides systematic analysis of DNA shape readout for many protein families. Congrats, Lin!

November 30, 2016
Our new Nature paper with the Leibniz Institute on Aging reveals role of Hoxa9 in muscle stem cell aging.

November 8, 2016
Our recent Dror et al. Genome Res. paper received a RECOMB/ISCB Top-10 Paper Award in regulatory and systems genomics in 2015/16.

August 31, 2016
Carolina defended her Ph.D. thesis with flying colors. Congratulations, Carolina!

August 18, 2016
Our new paper proves the impact of DNA shape on in vivo TF binding based on 400 human ChIP-seq datasets.

August 16, 2016
Remo was promoted to Full Professor of Biological Sciences at USC. Fight on!

July 14, 2016
Remo was elected Head of Computational Biology and Bioinformatics at USC. Fight on!

June 6, 2016
Lin defended his Ph.D. thesis with flying colors. Congratulations, Lin!

May 4, 2016
Tsu-Pei received a competitive Enhancement Fellowship from the USC Graduate School. Congratulations, Tsu-Pei!

May 3, 2016
Lin received the highest honor for a USC graduate student, the PhD Achievement Award. Congratulations, Lin!

May 3, 2016
Remo was introduced as the incoming Vice Chair of the Department of Biological Sciences and Director of Biological Sciences Studies.

April 20, 2016
Remo presented our recent Zhou et al. PNAS paper as one of the few selected Highlights at the recent RECOMB conference.

April 19, 2016
Carolina received the Harrison M. Kurtz Award and Tsu-Pei the William E. Trusten Award. Congrats, Carolina and Tsu-Pei!.

April 6, 2016
Remo received the USC Mentoring award in the category mentoring of graduate students. Best award ever!

March 16, 2016
Remo received the ACS OpenEye Outstanding Junior Faculty Award in Computational Chemistry at the American Chemical Society National Meeting.

January 28. 2016
Remo received Tenure at USC and was promoted to Associate Professor. Fight on!

November 18, 2015
Our recent Abe et al. Cell and Zhou et al. PNAS papers were voted as RECOMB/ISCB Top Papers in regulatory and systems genomics in 2014/15.

Recent news

August 21-25, 2016
Symposium on Modeling Water and Solvation in Biochemistry: Developments and Applications, American Chemical Society National Meeting, Philadelphia, PA

July 5-8, 2016
Meeting on Measuring and Modeling Quantitative Sequence-Function Relationships, Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory, NY

April 17-21, 2016
RECOMB 2016 Conference, Santa Monica, CA

March 23, 2016
Leibniz Institute on Aging - Fritz Lipmann Institute, Jena, Germany

March 15-19, 2016
CSHL Meeting on Systems Biology: Global Regulation of Gene Expression, Cold Spring Harbor Laboratory, NY

March 7-10, 2016
Workshop on Regulatory Genomics and Epigenomics, Simons Institute for the Theory of Computing, UC Berkeley, Berkeley, CA

February 5-7, 2016
Bridge@USC and Michelson Center for Convergent Biosciences Retreat, Catalina Island, CA

January 31- February 5, 2016
Epigenomics 2016 Meeting, Rio Mar, Puerto Rico

January 19, 2016
Bioinformatics and Computational Biology Research Center, Cedars-Sinai Medical Center, Los Angeles, CA

Recent presentations

BISC 321 syllabus
Multidisciplinary Seminar: Science, Technology, and Society

BISC 577a syllabus
Computational Molecular Biology Laboratory