Long-range correlations between DNA bending sites: relation to the structure and dynamics of nucleosomes

It has been established that the precise positioning of nucleosomes on genomic DNA can be achieved, at least for a minority of them, through sequence-dependent processes. However, to what extent DNA sequences play a role in the positioning of the major part of nucleosomes is still debated. The aim of the present study is to examine to what extent long-range correlations (LRC) are related to the presence of nucleosomes. Using the wavelet transform technique, we perform a comparative analysis of the DNA text and of the corresponding bending profiles generated with curvature tables based on nucleosome positioning data. The exploration of a number of eukaryotic and bacterial genomes through the optics of the so-called "wavelet transform microscope" reveals a characteristic scale of 100-200 bp that separates two regimes of different LRC. Here, we focus on the existence of LRC in the small-scale regime (10-200 bp) which are actually observed in eukaryotic genomes, in contrast to their absence in eubacterial genomes. Analysis of viral DNA genomes shows that, like their host's genomes, eukaryotic viruses present LRC but eubacterial viruses do not. There is one exception for genomes of poxviruses (Vaccinia and Melamoplus sanguinipes) which do not replicate in the cell nucleus and do not exhibit LRC. No small-scale LRC are detected in the genomes of all examined RNA viruses, with the exception of retroviruses. These results together with the observation of LRC between particular sequence motifs known to participate in the formation of nucleosomes (e.g. AA dinucleotides) strongly suggest that the 10-200 bp LRC are a signature of the sequence-dependence of nucleosome positioning. Finally, we discuss possible interpretations of these LRC in terms of the physical mechanisms that might govern the positioning and the dynamics of the nucleosomes along the DNA chain through cooperative processes.     

Structural Mechanics of DNA Wrapping in the Nucleosome

Experimental X-ray crystal structures and a database of calculated structural parameters of DNA octamers were used in combination to analyse the mechanics of DNA bending in the nucleosome core complex. The 1kx5 X-ray crystal structure of the nucleosome core complex was used to determine the relationship between local structure at the base-step level and the global superhelical conformation observed for nucleosome-bound DNA. The superhelix is characterised by a large curvature (597°) in one plane and very little curvature (10°) in the orthogonal plane. Analysis of the curvature at the level of 10-step segments shows that there is a uniform curvature of 30° per helical turn throughout most of the structure but that there are two sharper kinks of 50° at ± 2 helical turns from the central dyad base pair. The curvature is due almost entirely to the base-step parameter roll. There are large periodic variations in roll, which are in phase with the helical twist and account for 500° of the total curvature. Although variations in the other base-step parameters perturb the local path of the DNA, they make minimal contributions to the total curvature. This implies that DNA bending in the nucleosome is achieved using the roll-slide-twist degree of freedom previously identified as the major degree of freedom in naked DNA oligomers. The energetics of bending into a nucleosome-bound conformation were therefore analysed using a database of structural parameters that we have previously developed for naked DNA oligomers. The minimum energy roll, the roll flexibility force constant and the maximum and minimum accessible roll values were obtained for each base step in the relevant octanucleotide context to account for the effects of conformational coupling that vary with sequence context. The distribution of base-step roll values and corresponding strain energy required to bend DNA into the nucleosome-bound conformation defined by the 1kx5 structure were obtained by applying a constant bending moment. When a single bending moment was applied to the entire sequence, the local details of the calculated structure did not match the experiment. However, when local 10-step bending moments were applied separately, the calculated structure showed excellent agreement with experiment. This implies that the protein applies variable bending forces along the DNA to maintain the superhelical path required for nucleosome wrapping. In particular, the 50° kinks are constraints imposed by the protein rather than a feature of the 1kx5 DNA sequence. The kinks coincide with a relatively flexible region of the sequence, and this is probably a prerequisite for high-affinity nucleosome binding, but the bending strain energy is significantly higher at these points than for the rest of the sequence. In the most rigid regions of the sequence, a higher strain energy is also required to achieve the standard 30° curvature per helical turn. We conclude that matching of the DNA sequence to the local roll periodicity required to achieve bending, together with the increased flexibility required at the kinks, determines the sequence selectivity of DNA wrapping in the nucleosome.     

基于DTW距离的DNA序列相似性分析

在DNA序列相似性的研究中,通常采用的动态规划算法对空位罚分函数缺乏理论依据而带有主观性,从而取得不同的结果,本文提出了一种基于DTW（Dynamic Time Warping,动态时间弯曲）距离的DNA序列相似性度量方法可以解决这一问题．通过DNA序列的图形表示把DNA序列转化为时间序列,然后计算DTW距离来度量序列相似度以表征DNA序列属性,得到能够比较DNA序列相似性度量方法,并用这个方法比较分析了七种东亚钳蝎神经毒素（Buthusmartensi Karsch neurotoxin）基因序列的相似性,验证了该度量方法的有效性和准确性．     

Epigenetic Basis of Regeneration: Analysis of Genomic DNA Methylation Profiles in the MRL/MpJ Mouse

Epigenetic regulation plays essential role in cell differentiation and dedifferentiation, which are the intrinsic processes involved in regeneration. To investigate the epigenetic basis of regeneration capacity, we choose DNA methylation as one of the most important epigenetic mechanisms and the MRL/MpJ mouse as a model of mammalian regeneration known to exhibit enhanced regeneration response in different organs. We report the comparative analysis of genomic DNA methylation profiles of the MRL/MpJ and the control C57BL/6J mouse. Methylated DNA immunoprecipitation followed by microarray analysis using the Nimblegen ‘3 × 720 K CpG Island Plus RefSeq Promoter’ platform was applied in order to carry out genome-wide DNA methylation profiling covering 20 404 promoter regions. We identified hundreds of hypo- and hypermethylated genes and CpG islands in the heart, liver, and spleen, and 37 of them in the three tissues. Decreased inter-tissue diversification and the shift of DNA methylation balance upstream the genes distinguish the genomic methylation patterns of the MRL/MpJ mouse from the C57BL/6J. Homeobox genes and a number of other genes involved in embryonic morphogenesis are significantly overrepresented among the genes hypomethylated in the MRL/MpJ mouse. These findings indicate that epigenetic patterning might be a likely molecular basis of regeneration capability in the MRL/MpJ mouse.     

基于DNA序列数据挖掘算法研究

引入数据挖掘技术,研究DNA序列数据内在规律性,并给出DNA序列分类问题的算法．综合考虑碱基组的出现概率以及相邻氨基酸之间的关系,从DNA序列片段的个案中密码子分布密度角度出发,提取出已知类别的DNA序列片段的特征;应用分类的逐步判别分析方法,剔除判别能力不显著的变量,给出DNA序列分类的判别函数．仿真结果表明,该算法具有分类计算公式简单且分类结果精度的优点．     

Genomic structure and sequence variation of a 3.3-kb repeat DNA element of the kangaroo rat, Dipodomys ordii

The genomic structure and sequence variation of a 3.3-kb repeat DNA element, representing 5% of the genome of the kangaroo rat Dipodomys ordii, has been investigated. Most of the repeats are arranged in tandem arrays of 50 kb or more. Thirteen randomly selected genomic clones have been mapped with twelve restriction enzymes. The frequency of sequence divergence in the genomic clones is 0.5%. The clone maps and the genomic structure studies have permitted the characterization of a number of variant members of the 3.3-kb repeat family. The genomic organization of the repeat resembles that for repeated DNAs found in large tandem arrays or satellites.     

Some Probabilistic Results on the Nonrandomness of Simple Sequence Repeats in DNA Sequences

Some probabilistic results on simple sequence repeats (SSRs) in DNA sequences are derived and used to quantify the nonrandomness of SSRs as an index of nonrandomness. The applicability of the index of nonrandomness is illustrated using several examples from the literature on selected human diseased genes.     

Wavelet Analysis of DNA Walks on the Human and Chimpanzee MAGE/CSAG-palindromes

The palindrome is one class of symmetrical duplications with reverse complementary characters,which is widely distributed in many organisms.Graphical representation of DNA sequence provides a simple way of viewing and comparing various genomic structures.Through 3-D DNA walk analysis,the similarity and differences in nucleotide composition,as well as the evolutionary relationship between human and chimpanzee MAGE/CSAG-palindromes,can be clearly revealed.Further wavelet analysis indicated that duplicated segments have irregular patterns compared to their surrounding sequences.However,sequence similarity analysis suggests that there is possible common ancestor between human and chimpanzee MAGE/CSAG-palindromes.Based on the specific distribution and orientation of the repeated sequences,a simple possible evolutionary model of the palindromes is suggested,which may help us to better understand the evolutionary course of the genes and the symmetrical sequences.     

Integrative Structural Investigation on the Architecture of Human Importin4_Histone H3/H4_Asf1a Complex and Its Histone H3 Tail Binding

Importin4 transports histone H3/H4 in complex with Asf1a to the nucleus for chromatin assembly. Importin4 recognizes the nuclear localization sequence located at the N-terminal tail of histones. Here, we analyzed the structures and interactions of human Importin4, histones and Asf1a by cross-linking mass spectrometry, X-ray crystallography, negative-stain electron microscopy, small-angle X-ray scattering and integrative modeling. The cross-linking mass spectrometry data showed that the C-terminal region of Importin4 was extensively cross-linked with the histone H3 tail. We determined the crystal structure of the C-terminal region of Importin4 bound to the histone H3 peptide, thus revealing that the acidic patch in Importin4 accommodates the histone H3 tail, and that histone H3 Lys14 contributes to the interaction with Importin4. In addition, we show that Asf1a modulates the binding of histone H3/H4 to Importin4. Furthermore, the molecular architecture of the Importin4_histone H3/H4_Asf1a complex was produced through an integrative modeling approach. Overall, this work provides structural insights into how Importin4 recognizes histones and their chaperone complex.     

Loss of Introns Along the Evolutionary Diversification Pathway of Snake Venom Disintegrins Evidenced by Sequence Analysis of Genomic DNA from <Emphasis Type="Italic">Macrovipera lebetina transmediterranea</Emphasis> and <Emphasis Type="Italic">Echis ocellatus</Emphasis>

Analysis of cDNAs from Macrovipera lebetina transmediterranea (Mlt) and Echis ocellatus (Eo) venom gland libraries encoding disintegrins argued strongly for a common ancestry of the messengers of short disintegrins and those for precursors of dimeric disintegrin chains. We now report the sequence analysis of disintegrin-coding genes from these two vipers. Genomic DNAs for dimeric disintegrin subunits Ml_G1 and Ml_G2 (Mlt) and Eo_D3 (Eo) contain single 1-kb introns exhibiting the 5′-GTAAG (donor)/3′-AG (acceptor) consensus intron splicing signature. On the other hand, the short RTS-disintegrins Ml_G3 (Mlt) and Eo_RTS (Eo) and the short RGD-disintegrin ocellatusin (Eo) are transcribed from intronless genomic DNA sequences, indicating that the evolutionary pathway leading to the emergence of short disintegrins involved the removal of all intronic sequences. The insertion position of the intron within Ml_G1, Ml_G2, and Eo_D3 is conserved in the genes for vertebrate ADAM (A disintegrin and metalloproteinase) protein disintegrin-like domains and within the gene for the medium-size snake disintegrins halystatins 2 and 3. However, a comparative analysis of currently available disintegrin(-like) genes outlines the view that a minimization of both the gene organization and the protein structure underlies the evolution of the snake venom disintegrin family. [Reviewing Editor: Dr. Bryan Fry] Amine Bazaa and Paula Juárez contributed equally to this work and may both be considered first authors.