Juozas Gordevičius

Epigenetic markers of prostate cancer in plasma circulating DNA

Epigenetic differences are a common feature of many diseases, including cancer, and disease-associated changes have even been detected in bodily fluids. DNA modification studies in circulating DNA (cirDNA) may lead to the development of specific non-invasive biomarkers. To test this hypothesis, we investigated cirDNA modifications in prostate cancer patients with locally confined disease (n = 19), in patients with benign prostate hyperplasias (n = 20) and in men without any known prostate disease (n = 20). This initial discovery screen identified 39 disease-associated changes in cirDNA modification, and seven of these were validated using the sodium bisulfite-based mapping of modified cytosines in both the discovery cohort and an independent 38-patient validation cohort. In particular, we showed that the DNA modification of regions adjacent to the gene encoding ring finger protein 219 distinguished prostate cancer from benign hyperplasias with good sensitivity (61%) and specificity (71%). We also showed that repetitive sequences detected in this study were meaningful, as they indicated a highly statistically significant loss of DNA at the pericentromeric region of chromosome 10 in prostate cancer patients (p = 1.8 × 10(-6)). Based on these strong univariate results, we applied machine-learning techniques to develop a multi-locus biomarker that correctly distinguished prostate cancer samples from unaffected controls with 72% accuracy. Lastly, we used systems biology techniques to integrate our data with publicly available DNA modification and transcriptomic data from primary prostate tumors, thereby prioritizing genes for further studies. These data suggest that cirDNA epigenomics are promising source for non-invasive biomarkers.

DNA unmethylome profiling by covalent capture of CpG sites

Dynamic patterns of cytosine-5 methylation and successive hydroxylation are part of epigenetic regulation in eukaryotes, including humans, which contributes to normal phenotypic variation and disease risk. Here we present an approach for the mapping of unmodified regions of the genome, which we call the unmethylome. Our technique is based on DNA methyltransferase-directed transfer of activated groups and covalent biotin tagging of unmodified CpG sites followed by affinity enrichment and interrogation on tiling microarrays or next generation sequencing. Control experiments and pilot studies of human genomic DNA from cultured cells and tissues demonstrate that, along with providing a unique cross-section through the chemical landscape of the epigenome, the methyltransferase-directed transfer of activated groups-based approach offers high precision and robustness as compared with existing affinity-based techniques.

Lactase nonpersistence is directed by DNA-variation-dependent epigenetic aging

The inability to digest lactose, due to lactase nonpersistence, is a common trait in adult mammals, except in certain human populations that exhibit lactase persistence. It is not known how the lactase gene is dramatically downregulated with age in most individuals but remains active in some individuals. We performed a comprehensive epigenetic study of human and mouse small intestines, by using chromosome-wide DNA-modification profiling and targeted bisulfite sequencing. Epigenetically controlled regulatory elements accounted for the differences in lactase mRNA levels among individuals, intestinal cell types and species. We confirmed the importance of these regulatory elements in modulating lactase mRNA levels by using CRISPR–Cas9-induced deletions. Genetic factors contribute to epigenetic changes occurring with age at the regulatory elements, because lactase-persistence and lactase-nonpersistence DNA haplotypes demonstrated markedly different epigenetic aging. Thus, genetic factors enable a gradual accumulation of epigenetic changes with age, thereby influencing phenotypic outcome.

Clustering visually similar web page elements for structured web data extraction

We propose a novel approach for extraction of structured web data called ClustVX. It clusters visually similar web page elements by exploiting their visual formatting and structural features. Clusters are then used to derive extraction rules. The experimental evaluation results of ClustVX system on three publicly available benchmark data sets outperform state-of-the-art structured data extraction systems.

Cytosine modifications exhibit circadian oscillations that are involved in epigenetic diversity and aging

Circadian rhythmicity governs a remarkable array of fundamental biological functions and is mediated by cyclical transcriptomic and proteomic activities. Epigenetic factors are also involved in this circadian machinery; however, despite extensive efforts, detection and characterization of circadian cytosine modifications at the nucleotide level have remained elusive. In this study, we report that a large proportion of epigenetically variable cytosines show a circadian pattern in their modification status in mice. Importantly, the cytosines with circadian epigenetic oscillations significantly overlap with the cytosines exhibiting age-related changes in their modification status. Our findings suggest that evolutionary advantageous processes such as circadian rhythmicity can also contribute to an organism’s deterioration.While epigenetic factors have been implicated in the circadian rhythm, the detection of circadian cytosine modifications has remained elusive. Here the authors identify a large number of epigenetically variable cytosines that show circadian oscillations in their modification status in mice.

A Greedy Approach Towards Parsimonious Temporal Aggregation

Temporal aggregation is a crucial operator in temporal databases and has been studied in various flavors. In instant temporal aggregation (ITA) the aggregate value at time instant t is computed from the tuples that hold at t. ITA considers the distribution of the input data and works at the smallest time granularity, but the result size depends on the input timestamps and can get twice as large as the input relation. In span temporal aggregation (STA) the user specifies the timestamps over which the aggregates are computed and thus controls the result size. In this paper we introduce a new temporal aggregation operator, called greedy parsimonious temporal aggregation (PTAg), which combines features from ITA and STA. The operator extends and approximates ITA by greedily merging adjacent tuples with similar aggregate values until the number of result tuples is sufficiently small, which can be controlled by the application. Thus, PTAg considers the distribution of the data and allows to control the result size. Our empirical evaluation on real world data shows good results: considerable reductions of the result size introduce small errors only.

Tethered Oligonucleotide-Primed Sequencing, TOP-Seq: A High-Resolution Economical Approach for DNA Epigenome Profiling

Modification of CG dinucleotides in DNA is part of epigenetic regulation of gene function in vertebrates and is associated with complex human disease. Bisulfite sequencing permits high-resolution analysis of cytosine modification in mammalian genomes; however, its utility is often limited due to substantial cost. Here, we describe an alternative epigenome profiling approach, named TOP-seq, which is based on covalent tagging of individual unmodified CG sites followed by non-homologous priming of the DNA polymerase action at these sites to directly produce adjoining regions for their sequencing and precise genomic mapping. Pilot TOP-seq analyses of bacterial and human genomes showed a better agreement of TOP-seq with published bisulfite sequencing maps as compared to widely used MBD-seq and MRE-seq and permitted identification of long-range and gene-level differential methylation among human tissues and neuroblastoma cell types. Altogether, we propose an affordable single CG-resolution technique well suited for large-scale epigenome studies.

Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients

Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20% to 40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance. Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients. Results: Thirty cytosines showed significant modification differences (FDR Q < 0.05) between AA-sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA treatment, but such variation returned to initial levels in the later phases of treatment. Conclusions: Our findings provide a list of potential biomarkers for predicting AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients. Clin Cancer Res; 24(14); 3317–24. ©2018 AACR.

Ranking of evolving stories through meta-aggregation

In this paper we focus on the problem of ranking news stories within their historical context by exploiting their content similarity. We observe that news stories evolve and thus have to be ranked in a time and query dependent manner. We do this in two steps. First, the mining step discovers metastories, which constitute meaningful groups of similar stories that occur at arbitrary points in time. Second, the ranking step uses well known measures of content similarity to construct implicit links among all metastories, and uses them to rank those metastories that overlap the time interval provided in a user query. We use real data from conventional and social media sources (weblogs) to study the impact of different meta-aggregation techniques and similarity measures in the final ranking. We evaluate the framework using both objective and subjective criteria, and discuss the selection of clustering method and similarity measure that lead to the best ranking results.