Linking chromatin composition and structural dynamics at the nucleosome level
Nucleosomes are fundamental units of chromatin compaction, which organize ∼200 DNA base pairs using an octamer of histone proteins. Their ubiquitous presence in the cell nucleus since the first eukaryotes compelled the chromatin machinery to coevolve and learn how to exploit various modes of nucleosome dynamics and sense differences in nucleosome composition. Alterations to histone or DNA sequences, post-translational modifications (PTM) of histones, recruitment of chromatin proteins modulate nucleosome dyn amics and provide epigenetic regulation to the DNA processing pathways (transcription, replication, repair, etc.). Our understanding of this complex interplay between nucleosome composition, dynamics and functioning is constantly evolving through new insights and discoveries. In this review, we highlight recent contributions to the field while attempting to organize them in a unified framework.
We trained Random Forest model to recognize patterns of nucleosome and non-B DNA structures, considered as potential nucleosome barriers in the mouse genome. We showed that among four types of structures – Z-DNA, H-DNA, G-Quadruplexes and SIDD regions – recognition of G-Quadruplexes and H-DNA showed the best performance.
Non-B DNA structures have a great potential to form and influence various genomic processes including transcription. One of the mechanisms of transcription regulation is nucleo- some positioning. Even though only B-DNA can be wrapped around a nucleosome, non-B DNA structures can compete with a nucleosome for a genomic location. Here we used perman- ganate/S1 nuclease footprinting data on non-B DNA structures, such as Z-DNA, H-DNA, G- quadruplexes and stress-induced duplex destabilization (SIDD) sites, together with MNase-seq data on nucleosome positioning in the mouse genome. We found three types of patterns of nucleosome positioning around non-B DNA structures: a structure is surrounded by nucleo- somes from both sides, from one side, or nucleosome free region. Machine learning models based on random forest and XGBoost algorithms were constructed to recognize DNA regions of 1kB length containing a particular pattern of nucleosome positioning for four types of DNA structures (Z-DNA, H-DNA, G-quadruplexes and SIDD sites) based on statistics of di- and tri- nucleotides. The best performance (94% of accuracy) was reached for G-quadruplexes while for other types of structures the accuracy was under 70%. We conclude that 1kB regions con- taining G-quadruplexes have distinct compositional properties, and this fact points to preferen- tial locations of such pattern in the genome and requires further investigation. For other DNA structures a region composition is not a sufficient predictive factor and one should take into account other physical and structural DNA properties to improve nucleosome-DNA-structure pattern recognition.
Reply to Pattison's critique of our 2006 article in which we suggested an apartheid-type social structure in post-immigration England (5th - 8th centuries AD)
Non-B DNA structures have a great potential to form and influence various genomic processes including transcription. One of the mechanisms of transcription regulation is nucleosome positioning. Even though only B-DNA can be wrapped around a nucleosome, non-B DNA structures can compete with a nucleosome for a genomic location. Here we used permanganate/S1 nuclease footprinting data on non-B DNA structures, such as Z-DNA, H-DNA, G-quadruplexes and stress-induced duplex destabilization (SIDD) sites, together with MNase-seq data on nucleosome positioning in the mouse genome. We found three types of patterns of nucleosome positioning around non-B DNA structures: a structure is surrounded by nucleosomes from both sides, from one side, or nucleosome free region. Machine learning models based on random forest and XGBoost algorithms were constructed to recognize DNA regions of 1kB length containing a particular pattern of nucleosome positioning for four types of DNA structures (Z-DNA, H-DNA, G-quadruplexes and SIDD sites) based on statistics of di- and tri-nucleotides. The best performance (94% of accuracy) was reached for Gquadruplexes while for other types of structures the accuracy was under 70%. We conclude that 1kB regions containing Gquadruplexes have distinct compositional properties, and this fact points to preferential locations of such pattern in the genome and requires further investigation. Gene ontology analysis revealed that the genes intersecting with the discovered patterns are enriched in channel and transmembrane activity, transcription factor and receptor binding. The direction for further research is to study the distribution of the discovered patterns in different tissues to identify well-positioned and dynamic nucleosomes and reveal genes, regulated via DNA structures and nucleosome positioning.
We consider dense toroidal structures of DNA molecules in cells and viruses. The problem needs special studying. For one thing the space scale of the system being small one has to admit that such structures must be compact enough to accommodate a molecule of the DNA, for another the molecule should be easily accessible for various biochemical processes, for example replication. Theoretical treatment of the problem runs across substantial diculties, and there- fore there is a need for the experimental investigation of the DNA conformation in cells and viruses. The XFEL could be instrumental to that end.
Current estimates of the contribution of Continental migrants to the early medieval English population range from less than 10 000 to as many as 200 000. In contrast, recent studies based on Y-chromosome variation posit a considerably higher contribution to the modern English gene pool (50–100%). Historical evidence suggests that following the Anglo-Saxon transition, people of indigenous ethnicity were at an economic and legal disadvantage compared to those having Anglo-Saxon ethnicity. It is likely that such a disadvantage would lead to differential reproductive success. We examine the effect of differential reproductive success, coupled with limited intermarriage between distinct ethnic groups, on the spread of genetic variants. Computer simulations indicate that a social structure limiting intermarriage between indigenous Britons and an initially small Anglo-Saxon immigrant population provide a plausible explanation of the high degree of Continental male-line ancestry in England.
One of the key advances in genome assembly that has led to a significant improvement in contig lengths has been improved algorithms for utilization of paired reads (mate-pairs). While in most assemblers, mate-pair information is used in a post-processing step, the recently proposed Paired de Bruijn Graph (PDBG) approach incorporates the mate-pair information directly in the assembly graph structure. However, the PDBG approach faces difficulties when the variation in the insert sizes is high. To address this problem, we first transform mate-pairs into edge-pair histograms that allow one to better estimate the distance between edges in the assembly graph that represent regions linked by multiple mate-pairs. Further, we combine the ideas of mate-pair transformation and PDBGs to construct new data structures for genome assembly: pathsets and pathset graphs.
Papers about natural protection territories
Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta–gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding.
Neuronal nicotinic acetylcholine receptors (NNRs) of the α7 subtype have been shown to contribute to the release of dopamine in the nucleus accumbens. The site of action and the underlying mechanism, however, are unclear. Here we applied a circuit modeling approach, supported by electrochemical in vivo recordings, to clarify this issue. Modeling revealed two potential mechanisms for the drop in accumbal dopamine efflux evoked by the selective α7 partial agonist TC-7020. TC-7020 could desensitize α7 NNRs located predominantly on dopamine neurons or glutamatergic afferents to them or, alternatively, activate α7 NNRs located on the glutamatergic afferents to GABAergic interneurons in the ventral tegmental area. Only the model based on desensitization, however, was able to explain the neutralizing effect of coapplied PNU-120596, a positive allosteric modulator. According to our results, the most likely sites of action are the preterminal α7 NNRs controlling glutamate release from cortical afferents to the nucleus accumbens. These findings offer a rationale for the further investigation of α7 NNR agonists as therapy for diseases associated with enhanced mesolimbic dopaminergic tone, such as schizophrenia and addiction