Tolstorukov Laboratory

The long-term objective of the group is to understand genome function and evolution through computational approaches with a focus on epigenetics, developmental biology, and DNA mutability.

-- how transcriptional regulators identify their targets within a highly compacted genome of billions of nucleotides?
-- how genes are regulated with the reliability of a well-tuned machine across multiple tissues and developmental stages and what goes wrong in disease?
-- how chromatin organization varies in organisms with different genome complexities across the evolutionary scale?

Progress in high-throughput technologies, including next generation sequencing, allowed addressing these questions on genome scale. We develop methods for processing and analysis of such data and apply these methods to relevant biological and biomedical questions.

Specifically we are interested in how primary structure of chromatin – assembly of genomic DNA, RNA and proteins – mediates gene regulation in normal development and disease. The fundamental unit of chromatin organization – nucleosome – comprises about 150 bp of DNA and eight histone proteins of four types. There are two major roles that nucleosomes play in gene regulation: (i) nucleosomes control accessibility of DNA for interaction with transcription factors and (ii) they are subject to epigenetic modifications recognized by chromatin modifiers.

We study both these aspects of nucleosome organization. In the area of nucleosome positioning we focus on sequence-directed nucleosome positioning and the role of chromatin remodelers in establishing specific patterns of nucleosome occupancy at genomic regulatory regions such as gene starts and enhancers. In the area of nucleosome composition our focus is on histone variants, which replace major histones in a replication independent manner and often are essential for development. Recently we observed that a mammalian-specific variant H2A.Bbd is involved in regulation of both transcription and mRNA splicing and currently we are working towards further understanding of the role of histone variants in these two major pathways of gene expression.