Ilya Ioshikhes
Associate Professor

Research Interests:

My research interests cover a broad topic of gene regulation and include several related projects focusing on computational studies of chromatin, transcription factor (TF) interactions with DNA, promoter analysis, microRNAs and other topics. Other areas of bioinformatics are also part of my area of interests.

1) Transcriptional regulation of gene expression

Study of the regulation of gene expression is a fundamental problem in molecular biology. Transcriptional regulation is maintained through interactions of various transcription factors (TFs) between each other and with protein components of basal transcriptional complex including RNA polymerase. DNA sequences of the promoters, enhancers and other regulatory regions of the genes contain specific binding sites for the transcription factors and other components of the transcription machinery. These sites serve as a scaffold to bring various TFs to the close proximity to each other to facilitate their interaction and form active DNA-protein regulation complexes. In our research we focus on the investigation of different scenarios of the interaction between promoter and synergistic complex of transcription factors. We focus on statistical analysis and discovery of gene regulatory modules in the proximal promoter sequences and in long gene regulatory regions. Computational results should be experimentally verified. Our findings will be implemented in publicly available databases and software. Once it is completely developed, our technology will provide an efficient and powerful tool for computational analysis of promoter databases and complete genomes.

2) Nucleosome positioning as essential element of gene regulation

To be properly understood, promoter machinery must be studied in connection with chromatin context (nucleosome positioning and properties). Our most significant accomplishment in chromatin studies by sequence analysis is recent papers in Nature Genetics and Genome Research revealing nucleosome positioning for most of Yeast genome, followed by article in Nature about nucleosome organization in Drosophila genome. With ongoing avalanche of novel experimental data on nucleosome positioning, the aforementioned studies should represent a starting point much more profound planned research. Current and planned directions of our research in this area include analysis of following topics: Refinement of nucleosome sequence pattern on new experimental data; Comparative analysis of common nucleosomes and those with histone modifications (H2A.Z and others); Species-specific chromatin structure; Relationship of specific mechanisms of chromatin remodeling to alternative types of chromatin architecture; Chromatin structure in alternative promoters; Tissue-specific chromatin structure; Interaction of nucleosomes with TFs and other regulatory elements.

3) Micro-RNA regulation

Recently, it has been estimated that 30% of human genes may be regulated, in part, by a novel posttranscriptional mechanism involving microRNAs (miRNAs). MiRNAs are small RNA molecules that regulate gene expression primarily through translational repression. The functional importance of miRNAs is evidenced by the variety of biological processes in which they are implicated, including cell development and proliferation, apoptosis, metabolism, cell differentiation and morphogenesis. Medical significance of the miRNAs is conveyed through regulation of various genes related to cancer, cardiovascular function etc. Precise knowledge of the miRNA binding sites (targets) is essential for understanding of specific mechanisms of the posttranscriptional regulation. Algorithm and software development for computational recognition of the miRNA targets is one of the hottest and rapidly expanding areas of bioinformatics. Several algorithms are currently available, yet their performance is not always satisfactory. We suppose that the algorithm development in the area is still at its starting phase, often mechanistically adjusting for new needs mathematical apparatus and concepts from other areas of bioinformatics. Development of algorithms more specifically considering biophysical interaction between the miRNA and genomic/cDNA sequence is therefore the next necessary step in this area. We developed a novel miRNA target search algorithm, presumably more efficient than currently available algorithms. The algorithm uses strategy of sequence comparison specifically designed for miRNA/mRNA binding. It should be further optimized, verified on the experimental data and implemented in publicly available software.

Illustration of different possible scenarios of interaction between general TFs (TFIID and TFIIB) and core-promoter elements. The lower bar on each panel represents promoter area of DNA. TSS is placed at position +1. The bold black lines indicate interaction between the TFs or between the TFs and binding elements [12].

Nucleosome DNA AA/TT sequence pattern (a) and composite NPS profile of different classes of Yeast genes [6].

Selected Publications: