Start date – Nov 2016
1. The landscape of RNA-Chromatin Interactions.
This is an integration study of multiple NGS data sources to identify ribonucleoproteins at the chromatin-RNA interface, the chromatin context of RBP-RNA interactions, and the role of chromatin in RNA processing. The project includes research groups from UC Berkeley, UMass, MIT, and Center for Genomic Regulation in Barcelona. The contribution of my group is building spatio-temporal models of co- and post-transcriptional RNA processing using epigenetic data, eCLIP data, and in-house RNA structure prediction methods. These models are approached from several directions by using different machine learning methods, including convolutional neural networks (D. Svetlichnyy), logistic regression (D. Pervouchine), and random forests (K. Korovina and O. Pushkareva).
2. Association study of long-range RNA structure and pre-mRNA splicing.
This project is focused on conserved long-range intramolecular RNA-RNA interactions and their relation with long-range RNA processing events such as coordinated exon inclusion and exon skipping in distant parts of the gene. Previously, we found a strong evolutionarily conserved pattern of association between long-range intramolecular RNA structure and splicing. The continuation of this project is to test RNA-structure-based models of transcript rescue from premature cleavage and polyadenylation as well as capping and 5’-processing. We also benchmark our finding against novel methods for RNA structure probing, including ones that account for long-range intramolecular RNA-RNA interactions (N. Didkovskaya).
3. Evolution of regulatory RNA-structures that lead to mutually exclusive and mutually inclusive splicing patterns.
One class of regulatory RNA structures in eukaryotic genomes are associated with special types of alternative splicing events, e.g., mutually exclusive exons or mutually inclusive (array) exons. Mutually exclusive exons usually come as an array of 2+ exons, of which one and only one is included in the mRNA. Mutually inclusive exons are either included together or neither of them is included. Molecular mechanisms underlying mutually exclusive and mutually inclusive patterns often involve RNA structure. The origin of such events is likely related to genomic duplications which copy-and-paste different elements of RNA structure. The goal of this project is to describe the evolutionary mechanism which leads to the formation of mutually inclusive and mutually exclusive patterns (in collaboration with Bazykin lab).
4. The analysis of the functionality of annotated nonsense-mediated decay event.
The nonsense mediated decay (NMD) pathway has evolved to destroy eukaryotic transcripts with premature translation termination codons. However, it is quite often implicated in splicing-mediated regulation of gene expression. For instance, a splicing factor binds its own pre-mRNA to induce inclusion of a poisonous exons leading to premature translation termination and degradation by NMD. The aim of this project is to identify the regulatory potential of NMD in human genes as well as to find to what extent this mechanism is widespread in human genes (Adam Frankish and Yaroslav Popov).
5. In-house pipelines for NGS data analysis.
This is an initiative to build a set of in-house utilities (a bioinformatics toolbox) for the efficient analysis, storage, and processing of RNA-seq data. One part of it is the IPSA package (Integrative Pipeline for Splicing Analyses) that is currently under development within the framework of projects in the Center for Genomic Regulation in Barcelona. The aim is to extend it to a library of elementary operations (mapping to the reference, lift-over, data-type conversion, phasing allelic information etc) on standardized data types.
6. The role of metabolic genes in creating slow dynamic oscillatory patterns in rat entorhinal cortex.
In 2006 my colleagues from Leeds University (UK) and I have built a mathematical model of slow-wave oscillation on rat neocortex in response to ischemic conditions under the application of kainate. We found that slow-wave oscillation was dependent on metabolic genes and reacted to the blockade of ATP-sensitive potassium channels (Kir6.2). A similar pattern of oscillatory activity is known for pancreatic beta cell which also uses Kir6.2 protein to discharge insulin vesicles in response to glucose stimulation. Accordingly, the project is to compare the expression of gene networks in human pancreas and in the neocortex (specifically, entorhinal cortex) and to understand the common origin and evolution of action potential-evoking circuits in these two very different organs.
7. Molecular markers of intra-abdominal hypertension and to development of abdominal compartment syndrome in newborns.
This is a collaboration with a clinical study carried out by I.M. Sechenov First Moscow State Medical University regarding the abdominal compartment syndrome. The contribution of my group is the statistical analysis of a set of most promising biomarkers for detecting the earliest signs of kidney injury in abdominal compartment syndrome. (collaboration with Dr. I. Budnik)