Vladimir Rogojin

Early Maternal Alcohol Consumption Alters Hippocampal DNA Methylation, Gene Expression and Volume in a Mouse Model

The adverse effects of alcohol consumption during pregnancy are known, but the molecular events that lead to the phenotypic characteristics are unclear. To unravel the molecular mechanisms, we have used a mouse model of gestational ethanol exposure, which is based on maternal ad libitum ingestion of 10% (v/v) ethanol for the first 8 days of gestation (GD 0.5-8.5). Early neurulation takes place by the end of this period, which is equivalent to the developmental stage early in the fourth week post-fertilization in human. During this exposure period, dynamic epigenetic reprogramming takes place and the embryo is vulnerable to the effects of environmental factors. Thus, we hypothesize that early ethanol exposure disrupts the epigenetic reprogramming of the embryo, which leads to alterations in gene regulation and life-long changes in brain structure and function. Genome-wide analysis of gene expression in the mouse hippocampus revealed altered expression of 23 genes and three miRNAs in ethanol-exposed, adolescent offspring at postnatal day (P) 28. We confirmed this result by using two other tissues, where three candidate genes are known to express actively. Interestingly, we found a similar trend of upregulated gene expression in bone marrow and main olfactory epithelium. In addition, we observed altered DNA methylation in the CpG islands upstream of the candidate genes in the hippocampus. Our MRI study revealed asymmetry of brain structures in ethanol-exposed adult offspring (P60): we detected ethanol-induced enlargement of the left hippocampus and decreased volume of the left olfactory bulb. Our study indicates that ethanol exposure in early gestation can cause changes in DNA methylation, gene expression, and brain structure of offspring. Furthermore, the results support our hypothesis of early epigenetic origin of alcohol-induced disorders: changes in gene regulation may have already taken place in embryonic stem cells and therefore can be seen in different tissue types later in life.

COMPUTATIONAL POWER OF INTRAMOLECULAR GENE ASSEMBLY

The process of gene assembly in ciliates, an ancient group of organisms, is one of the most complex instances of DNA manipulation known in any organism. Three molecular operations Id, hi, and dlad have been postulated for the gene assembly process. We propose in this paper a mathematical model for contextual variants of Id and dlad on strings: recombinations can be done only if certain contexts are present. We prove that the proposed model is Turing-universal.

Patterns of simple gene assembly in ciliates

The intramolecular model for gene assembly in ciliates considers three operations, ld, hi, and dlad that can assemble any gene pattern through folding and recombination: the molecule is folded so that two occurrences of a pointer (short nucleotide sequence) get aligned and then the sequence is rearranged through recombination of pointers. In general, the sequence rearranged by one operation can be arbitrarily long and consist of many coding and noncoding blocks. We consider in this paper simple variants of the three operations, where only one coding block is rearranged at a time. We characterize in this paper the gene patterns that can be assembled through these variants. Our characterization is in terms of signed permutations and dependency graphs. Interestingly, we show that simple assemblies possess rather involved properties: a gene pattern may have both successful and unsuccessful assemblies and also more than one successful assembling strategy.

Accepting splicing systems

In this paper, we propose a novel approach to splicing systems, namely we consider them as accepting devices. Two ways of iterating the splicing operation and two variants of accepting splicing system are investigated. Altogether, we obtain four models, which are compared with each other as well as with the generating splicing systems from the computational power point of view. Several decision problems concerning the accepting splicing systems are discussed.

The Phosphorylation of the Heat Shock Factor as a Modulator for the Heat Shock Response

The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis ofhspis highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation ofhsfs. Experimental evidence shows a connection between the hyper-phosphorylation ofhsfs and the transactivation of thehsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.

The parallel complexity of signed graphs: Decidability results and an improved algorithm

We consider a graph-based model for the process of gene assembly in ciliates, as proposed in [A. Ehrenfeucht, T. Harju, I. Petre, D. M. Prescott, G. Rozenberg, Computation in Living Cells: Gene Assembly in Ciliates, Springer, 2003]. The model consists of three operations, each reducing the order of the signed graph. Reducing the graph to the empty graph through a sequence of operations corresponds to assembling a gene. We investigate parallel reductions of a given signed graph, where the graph is reduced through a sequence of parallel steps. A parallel step consists of operations such that any of their sequential compositions are applicable to the current graph. We improve the basic exhaustive search algorithm reported in [A. Alhazov, C. Li, I. Petre, Computing the graph-based parallel complexity of gene assembly, Theoretical Computer Science, 2008 (in press)] to compute the parallel complexity of signed graphs. On the one hand, we reduce the number of sets of operations which should be checked for parallel applicability. On the other hand, we speed up the parallel applicability check procedure. We prove also that deciding whether a given parallel composition of operations is applicable to a given signed graph is a coNP problem. Deciding whether the parallel complexity (the length of a shortest parallel reduction) of a signed graph is bounded by a given constant is in NP^N^P.

SUCCESSFUL ELEMENTARY GENE ASSEMBLY STRATEGIES

We study elementary gene assembly in ciliates. During sexual reproduction, broken and shuffled gene segments in micronuclei get assembled into contiguous macronuclear genes. We consider here a restricted version of the intramolecular model (called elementary), where at most one gene segment is involved at a time (either inverted, or translocated). Not all gene patterns may be assembled by elementary operations, and not all assembly strategies are successful. For a given gene pattern, we characterize in this paper all successful translocation-only elementary assemblies. We also estimate the number of such assemblies. We solve the problem in terms of graphs and permutations.

Identification of genetic markers with synergistic survival effect in cancer

BackgroundCancers are complex diseases arising from accumulated genetic mutations that disrupt intracellular signaling networks. While several predisposing genetic mutations have been found, these individual mutations account only for a small fraction of cancer incidence and mortality. With large-scale measurement technologies, such as single nucleotide polymorphism (SNP) microarrays, it is now possible to identify combinatorial effects that have significant impact on cancer patient survival.ResultsThe identification of synergetic functioning SNPs on genome-scale is a computationally daunting task and requires advanced algorithms. We introduce a novel algorithm, Geninter, to identify SNPs that have synergetic effect on survival of cancer patients. Using a large breast cancer cohort we generate a simulator that allows assessing reliability and accuracy of Geninter and logrank test, which is a standard statistical method to integrate genetic and survival data.ConclusionsOur results show that Geninter outperforms the logrank test and is able to identify SNP-pairs with synergetic impact on survival.

The phosphorylation of the heat shock factor as a modulator for the heat shock response

The heat shock response is a well-conserved defence mechanism against the accumulation of misfolded proteins due to prolonged elevated heat. The cell responds to heat shock by raising the levels of heat shock proteins (hsp), which are responsible for chaperoning protein refolding. The synthesis of hsp is highly regulated at the transcription level by specific heat shock (transcription) factors (hsf). One of the regulation mechanisms is the phosphorylation of hsfs. Experimental evidence shows a connection between the hyper-phosphorylation of hsfs and the transactivation of the hsp-encoding genes. In this paper, we incorporate several (de)phosphorylation pathways into an existing well-validated computational model of the heat shock response. We analyze the quantitative control of each of these pathways over the entire process. For each of these pathways we create detailed computational models which we subject to parameter estimation in order to fit them to existing experimental data. In particular, we find conclusive evidence supporting only one of the analyzed pathways. Also, we corroborate our results with a set of computational models of a more reduced size.

Decision problem for shuffled genes

We consider a permutation-based model for the gene assembly process in ciliates. We give a procedure to decide whether a given micronuclear molecule may be assembled by using only simple dlad operations. We solve the problem based on a notion of dependency graph.