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Nanobiology Applications of the Molecular Modeling Core at the CCR Nanobiology Program (CCRNP), CCR, NCI/FCRDC, NCI, NIH:


Discovering Functional Structured RNAs (FSR) in Genomes


The RNA folding and modeling unit at CCRNP will develop novel sophisticated algorithms by integrating statistical and computational tools of RNA folding, pattern search, sequence and structure comparison for finding FSR, non-coding RNAs (ncRNAs), and RNA structural motifs. The unit not only provides advanced computational tools to NCI investigators but also promotes collaborations with Experimental Scientists to characterize essential principles of underlying biological processes and the knowledgeable discovery of highly complex data sets. Current collaborations have emphasized on post-transcriptional gene regulation and discoveries of FSRs and RNA structure motifs involved in gene expression. It also provide free consultation and collaboration services in molecular modeling and discovery of functional RNA structural elements in genomes to CCR scientists.


Background: With the completion of genome-sequencing projects and rapid advances in computational biology and bioinformatics, a major challenge for us is to understand gene function and regulation from enormous genomic sequences. Achieving this goal requires combined efforts of bioinformaticists and molecular biologists. Such integrative approaches hold promise for elucidating fundamental principles of gene function, post-transcriptional regulation and RNA-based regulation of gene expressions. They also enable us to discover structural features in RNA that often are correlated with important functions, and identify potential therapeutic targets.

Recent advances in studies of ncRNAs and RNA interference (RNAi) indicate that RNA is more than a messenger between genome and protein. The ncRNAs are involved in various regulatory mechanisms of gene expression at multiple levels. Works of RNA-based regulation have also revealed important homology-based mechanisms for sequence-specific RNA degradation and RNA-directed DNA methylation and modification by aberrant RNAs and dsRNAs. Well documented instances include transcriptional mediation, RNA processing and modification, mRNA stability and localization, and translation of mRNA into protein. FSRs that can perform the regulatory activity comprise transfer RNA, ribosomal RNAs, self-cleavage ribozymes, metabolite-responsive ribozyme, small micro-RNAs (miRNAs), and various RNA regulatory elements, such as iron-responsive element (IRE) in the non-coding region (NCR) of ferritin mRNAs. internal ribosome entry sequence in the 5' NCR and cis-acting RNA elements involving in nuclear mRNA export, such as Rev response element (RRE) of HIV-1 and constitutive transport element (CTE) of Mason-Pfizer monkey virus.

It is conceivable that there are a large number of various FSRs in each genome. The FSR molecules are expected to be characterized by various structural motifs represented by specific combinations of base pairings and conserved nucleotides (nt) in the loop regions. Many mRNAs have long 3'UTRs that contain unusual well-ordered RNA structures that may be implicated in stability, expression, localization, and development.


Goals of the Program:

  • Development of novel sophisticated algorithms in RNA folding, analyses of RNA structures and discovery of ncRNAs, RNA motifs and RNA functional elements.
  • a) Develop computing algorithms for predicting common RNA structures from a set of related RNA sequences by integrating RNA folding, phylogenetical analysis, RNA structural comparison, and various algorithms such as dynamic programming and genetic algorithms.

    b) Develop sophisticated search tools for detecting homologous structured RNAs in genomic sequences based on the detailed information of sequence and higher-ordered RNA structure. Such novel algorithm will completely differ from other currently used search algorithms because it takes structural constraints of the query RNA in detail, including each base-pairs in the RNA structure and each nucleotide in the single strands. Also, the homologous structured RNAs in genomes are strictly inferred from a robust statistical distribution of a quantitative measure, maximal similarity score that was computed by the comparison of structure morphology.

    c) Develop novel algorithms for finding local well-ordered structures that are both the thermodynamic stable and uniquely folded in genomic sequences. The unusual well-ordered structures are expected to be correlated with important functions.

    d) Develop computing protocols for discoveries of unknown FSR, ncRNA and conserved RNA structural motif.

    e) Develop computing protocols for finding potential targets of regulating RNAs in genomes.

  • Data mining of RNA functional elements in RNA sequences.
  • a) We emphasize our research on RNA-based gene regulation, post-transcriptional gene regulation and prediction of functional RNA structures and dsRNAs.

    b) Determination of the common RNA structure for functional RNA molecules and ncRNAs.

  • Nanoparticle study of RNA building block.
  • To enhance the therapeutic treatment of cancer, it is important to develop multifunctional, targeted RNA nanoparticles capable to bypassing biological barries to deliver the therapeutic agents directly to cancer cells. It is our goal to discover RNA building blocks that can be used in bottom-up assembly in nanotechnology.

  • Provide flexible and powerful computational tools and advice to NIH investigators on various topics associated with RNA folding and RNA structural analysis.
  • We will establish valuable resource for computation of RNA structure with facilitating the use of the resource by NIH scientists. Through our examples of successful collaborative projects it demonstrates that the combination of bench scientists and computational approaches with perfectly designed experiments yields fruitful results. We seek for collaborations, especially, with bench scientists.


Back to CCRNP Research Projects

For additional information please contact:

Shu-Yun Le
Staff Scientist
Center for Cancer Research Nanobiology Program (CCRNP)
CCR, NCI/FCRDC, NCI, NIH
Bldg. 469/Rm 145
Tel: (301) 846-5576
Fax: (301) 846-5598
shuyun@ncifcrf.gov


RNA Folding and Modeling at the CCRNP, Center for Cancer Research (CCR) National Cancer Institute, National Institutes of Health.