Advances in both experimental and computational biology are helping make exciting discoveries in many fields of biology and biomedicine today. Together, physical experiments and modeling are solving fundamental puzzles in biology as well as applying the findings to medicine and technology through molecular design, targeted therapies, and nanotechnology. The PI's computational biology /biophysics lab focuses on solving fundamental structural and dynamical questions concerning nucleic acids and their complexes (notably chromatin and RNA) in collaboration with experimentalists by innovative molecular models and computational methods using ideas from mathematics, computer science, and engineering, as well as biology and chemistry. This MIRA project would consolidate three NIGMS projects on chromatin structure, RNA design, and RNA structure prediction to advance our fundamental understanding of structure/function relationships for chromatin and RNA using multiscale models that bridge disparate scales to allow unprecedented applications regarding chromatin and RNA folding. For chromatin, the detailed atomic information on nucleosomes and long-range contact maps available from genome-wide experiments will be bridged by a hierarchy of tunable coarse-grained models to link atomic, mesoscale, and polymer models to investigate the epigenetic modulation of chromatin higher-order structure by gene looping mechanisms in cancer cells; these structural mechanisms for repression/ activation of transcription have translational ramifications through targeted re-expression of those silenced genes by chromatin loop dissolution for cancer therapy. For RNA, the general problem of poor predictions of RNA and RNA/protein tertiary motifs will be tackled by exploiting the drastic variable reduction and natural modularity of 2D graphs to combine efficient coarse-grained graph sampling, graph theory substructuring, and data-mining with improved handling of pseudoknots, kink-turns, and RNA-protein-binding motifs in our program RAGTOP. We will contribute to community efforts like RNA-puzzles; design novel RNAs for predicted, but yet undiscovered, RNA-like fold motifs to produce a atlas of modules for design; and design riboswitches with desired fluorescent properties, as sensors. These works, with support from leading experts in chromatin and RNA structure and function, will help advance fundamental areas of biology /biomedicine including genome biophysics, chromatin higher-order structure, gene expression, and cell development and differentiation and hence the targeted treatment of human diseases associated with aberrant gene expression, including cancers, genetic disorders, and degenerative diseases. The resulting multiscale computing paradigms are widely applicable to other biomolecular processes and will be shared with the community at large.
This project involves development and application of new multiscale computational methods to study the organization of chromosomes in the cell and the structure and activity of RNAs. A linking of the many relevant biological scales is essential for understanding the complex biological activities of these macromolecules in the cellular environment which affect fundamental processes including gene expression and cell differentiation and development. An improved understanding of these structures and dynamics of the genetic material (DNA) and of its RNA cousin, together will establishment of systematic methods for their study, advances the diagnosis and treatment of human diseases such as genetic syndromes, degenerative diseases, and cancers associated with chromosomal or epigenetic abnormalities through molecular design and targeted therapies.
| Jain, Swati; Bayrak, Cigdem S; Petingi, Louis et al. (2018) Dual Graph Partitioning Highlights a Small Group of Pseudoknot-Containing RNA Submotifs. Genes (Basel) 9: |
| Bascom, Gavin D; Schlick, Tamar (2018) Chromatin Fiber Folding Directed by Cooperative Histone Tail Acetylation and Linker Histone Binding. Biophys J 114:2376-2385 |
| Schlick, Tamar (2018) Adventures with RNA graphs. Methods 143:16-33 |
| Jain, Swati; Laederach, Alain; V Ramos, Silvia B et al. (2018) A pipeline for computational design of novel RNA-like topologies. Nucleic Acids Res 46:7040-7051 |
| Schlick, Tamar; Pyle, Anna Marie (2017) Opportunities and Challenges in RNA Structural Modeling and Design. Biophys J 113:225-234 |
| Bascom, Gavin; Schlick, Tamar (2017) Linking Chromatin Fibers to Gene Folding by Hierarchical Looping. Biophys J 112:434-445 |
| Jain, Swati; Schlick, Tamar (2017) F-RAG: Generating Atomic Coordinates from RNA Graphs by Fragment Assembly. J Mol Biol 429:3587-3605 |
