BackgroundEarly diagnosis of rheumatoid arthritis (RA) is crucial to providing effective therapy and often hampered by unspecific clinical manifestations. Elevated levels of extracellular circulating DNA (cirDNA) in patients with autoimmune disease were found to be associated with etiopathogenesis. To our knowledge, this is the first study to investigate the putative diagnostic use of cirDNA in RA and its association with disease activity.MethodsBlood samples were taken from 63 healthy subjects (HS) and 74 patients with RA. cirDNA was extracted from plasma and cell surface-bound cirDNA fractions (csbDNA). cirDNA concentration was measured by quantitative real-time polymerase chain reaction. Rheumatoid factor was analyzed by immunonephelometry, whereas C-reactive protein and anticitrullinated protein/peptide antibodies (ACPA) were detected by enzyme-linked immunosorbent assay.ResultsPlasma cirDNA was significantly elevated in patients with RA compared with HS (12.0 versus 8.4 ng/ml, p < 0.01). In contrast, nuclear csbDNA (n-csbDNA) was significantly decreased (24.0 versus 50.8 ng/ml, p < 0.01), whereas mitochondrial csbDNA (m-csbDNA) was elevated (1.44 × 106 copies/ml versus 0.58 × 106 copies/ml, p < 0.05) in RA. The combination of csbDNA (mitochondrial + nuclear) with ACPA reveals the best positive/negative likelihood ratios (LRs) for the discrimination RA from HS (LR+ 61.00, LR− 0.03) in contrast to ACPA (LR+ 9.00, LR− 0.19) or csbDNA (LR+ 8.00, LR− 0.18) alone.ConclusionsNuclear and mitochondrial cirDNA levels in plasma and on the surface of blood cells are modulated in RA. Combination of cirDNA values with ACPA can improve the serological diagnosis of RA.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1295-z) contains supplementary material, which is available to authorized users.

Late-replicating domains (intercalary heterochromatin) in the Drosophila genome display a number of features suggesting their organization is quite unique. Typically, they are quite large and encompass clusters of functionally unrelated tissue-specific genes. They correspond to the topologically associating domains and conserved microsynteny blocks. Our study aims at exploring further details of molecular organization of intercalary heterochromatin and has uncovered surprising heterogeneity of chromatin composition in these regions. Using the 4HMM model developed in our group earlier, intercalary heterochromatin regions were found to host chromatin fragments with a particular epigenetic profile. Aquamarine chromatin fragments (spanning 0.67% of late-replicating regions) are characterized as a class of sequences that appear heterogeneous in terms of their decompactization. These fragments are enriched with enhancer sequences and binding sites for insulator proteins. They likely mark the chromatin state that is related to the binding of cis-regulatory proteins. Malachite chromatin fragments (11% of late-replicating regions) appear to function as universal transitional regions between two contrasting chromatin states. Namely, they invariably delimit intercalary heterochromatin regions from the adjacent active chromatin of interbands. Malachite fragments also flank aquamarine fragments embedded in the repressed chromatin of late-replicating regions. Significant enrichment of insulator proteins CP190, SU(HW), and MOD2.2 was observed in malachite chromatin. Neither aquamarine nor malachite chromatin types appear to correlate with the positions of highly conserved non-coding elements (HCNE) that are typically replete in intercalary heterochromatin. Malachite chromatin found on the flanks of intercalary heterochromatin regions tends to replicate earlier than the malachite chromatin embedded in intercalary heterochromatin. In other words, there exists a gradient of replication progressing from the flanks of intercalary heterochromatin regions center-wise. The peculiar organization and features of replication in large late-replicating regions are discussed as possible factors shaping the evolutionary stability of intercalary heterochromatin.

The discovery of transposable elements (TEs) has raised the question of their role in host genomes. The experimental data accumulated over the last three decades has allowed scientists to draw conclusions on the role and behavior of TEs in genomes. It is currently known that the spontaneous rate of TE insertions in drosophila is 10 -4 -10 -5 events per site per genome per generation, which is one to two orders of magnitude higher than the rate of spontaneous recessive mutations. It is believed that most oligogenic (majorgenic) mutations result from TE insertion. Moreover, TEs can regulate the function and activity of major and minor genes, because they contain control system motifs and enhancers, which consist of several modules, and thus can bind to various transcription factors. Crossover between long terminal repeats can result in various types of chromosomal rearrangements: deletions, duplications, and inversions. Transposable elements can fill chromosome telomeres and take part in horizontal gene transfer. Various stress factors acting on genomes cre ate transposition explosions as a response. In this work we estimate the TE transposition induction rates in response to various external stress factors: cold and heat shock, ethanol vapor, and γ irradiation. We show that external stress factors increase the TE transposition rate to 10 -2 -10 -3 events per site per genome per gener ation, which is one to two orders of magnitude greater than the spontaneous transposition rate. Also, TE pat terns are significantly influenced by genetic factors: outbreeding, inbreeding, and selection. Thus, we con clude that the system of transposable elements in genomes is as substantial and universal as the SOS repara tion and hormonal control systems. It is reasonable to suggest that TEs act as receptors of stress signals, which initiate explosions of transpositional variation during critical phases of population evolution. This may cause a rapid adjustment of the specific homeostatic norm and, probably, speciation. We can thus state that the pres ence of TEs, in particular in eukaryotic genomes, allows a population to survive under dramatically altered environmental conditions. Therefore, we can suggest that TEs are directly involved in the expression of genes encoding traits in the course of selection and evolution.