scholarly journals Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline

2017 ◽  
Author(s):  
Vera B Kaiser ◽  
Colin A Semple
Keyword(s):  
Genome Instability ◽  
Large Fraction ◽  
Replication Timing ◽  
Basic Unit ◽  
Mutational Bias ◽  
Binding Motif ◽  
Chromatin Loop ◽  
Single Nucleotide Variants ◽  
Chromatin Loops ◽  
Evolutionary Innovation

ABSTRACTChromatin loops form a basic unit of interphase nuclear organisation, providing contacts between regulatory regions and target promoters, and forming higher level patterns defining self interacting domains. Recent studies have shown that mutations predicted to alter chromatin loops and domains are frequently observed in tumours and can result in the upregulation of oncogenes, but the combinations of selection and mutational bias underlying these observations remains unknown. Here, we explore the unusual mutational landscape associated with chromatin loop anchor points (LAPs), which are located at the base of chromatin loops and form a kinetic trap for cohesin. We show that LAPs are strongly depleted for single nucleotide variants (SNVs) in tumours, which is consistent with their relatively early replication timing. However, despite low SNV rates, LAPs emerge as sites of evolutionary innovation showing enrichment for structural variants (SVs). They harbour an excess of SV breakpoints in cancers, are prone to double strand breaks in somatic cells, and are bound by DNA repair complex proteins. Recurrently disrupted LAPs are often associated with genes annotated with functions in cell cycle transitions. An unexpectedly large fraction of LAPs (16%) also overlap known meiotic recombination hotspot (HSs), and are enriched for the core PRDM9 binding motif, suggesting that LAPs have been foci for diversity generated during recent human evolution. We suggest that the unusual chromatin structure at LAPs underlies the elevated SV rates observed, marking LAPs as sites of regulatory importance but also genomic fragility.

scholarly journals Predicting CTCF-mediated chromatin loops using CTCF-MP

2018 ◽  
Author(s):  
Ruochi Zhang ◽  
Yuchuan Wang ◽  
Yang Yang ◽  
Yang Zhang ◽  
Jian Ma
Keyword(s):  
Learning Algorithm ◽  
Three Dimensional ◽  
Cell Types ◽  
Ctcf Binding ◽  
Binding Motif ◽  
Chromatin Loop ◽  
Genomic Context ◽  
Motif Pair ◽  
Chromatin Loops ◽  
Single Cell Type

AbstractThe three dimensional organization of chromosomes within the cell nucleus is highly regulated. It is known that CTCF is an important architectural protein to mediate long-range chromatin loops. Recent studies have shown that the majority of CTCF binding motif pairs at chromatin loop anchor regions are in convergent orientation. However, it remains unknown whether the genomic context at the sequence level can determine if a convergent CTCF motif pair is able to form chromatin loop. In this paper, we directly ask whether and what sequence-based features (other than the motif itself) may be important to establish CTCF-mediated chromatin loops. We found that motif conservation measured by “branch-of-origin” that accounts for motif turn-over in evolution is an important feature. We developed a new machine learning algorithm called CTCF-MP based on word2vec to demonstrate that sequence-based features alone have the capability to predict if a pair of convergent CTCF motifs would form a loop. Together with functional genomic signals from CTCF ChIP-seq and DNase-seq, CTCF-MP is able to make highly accurate predictions on whether a convergent CTCF motif pair would form a loop in a single cell type and also across different cell types. Our work represents an important step further to understand the sequence determinants that may guide the formation of complex chromatin architectures.

scholarly journals Chromatin loop anchors contain core structural components of the gene expression machinery in maize

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stéphane Deschamps ◽  
John A. Crow ◽  
Nadia Chaidir ◽  
Brooke Peterson-Burch ◽  
Sunil Kumar ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Transcriptional Activity ◽  
Spatial Organization ◽  
Regulatory Elements ◽  
Open Chromatin ◽  
Maize Genome ◽  
Chromatin Loop ◽  
Structural Components ◽  
Chromatin Loops

Abstract Background Three-dimensional chromatin loop structures connect regulatory elements to their target genes in regions known as anchors. In complex plant genomes, such as maize, it has been proposed that loops span heterochromatic regions marked by higher repeat content, but little is known on their spatial organization and genome-wide occurrence in relation to transcriptional activity. Results Here, ultra-deep Hi-C sequencing of maize B73 leaf tissue was combined with gene expression and open chromatin sequencing for chromatin loop discovery and correlation with hierarchical topologically-associating domains (TADs) and transcriptional activity. A majority of all anchors are shared between multiple loops from previous public maize high-resolution interactome datasets, suggesting a highly dynamic environment, with a conserved set of anchors involved in multiple interaction networks. Chromatin loop interiors are marked by higher repeat contents than the anchors flanking them. A small fraction of high-resolution interaction anchors, fully embedded in larger chromatin loops, co-locate with active genes and putative protein-binding sites. Combinatorial analyses indicate that all anchors studied here co-locate with at least 81.5% of expressed genes and 74% of open chromatin regions. Approximately 38% of all Hi-C chromatin loops are fully embedded within hierarchical TAD-like domains, while the remaining ones share anchors with domain boundaries or with distinct domains. Those various loop types exhibit specific patterns of overlap for open chromatin regions and expressed genes, but no apparent pattern of gene expression. In addition, up to 63% of all unique variants derived from a prior public maize eQTL dataset overlap with Hi-C loop anchors. Anchor annotation suggests that < 7% of all loops detected here are potentially devoid of any genes or regulatory elements. The overall organization of chromatin loop anchors in the maize genome suggest a loop modeling system hypothesized to resemble phase separation of repeat-rich regions. Conclusions Sets of conserved chromatin loop anchors mapping to hierarchical domains contains core structural components of the gene expression machinery in maize. The data presented here will be a useful reference to further investigate their function in regard to the formation of transcriptional complexes and the regulation of transcriptional activity in the maize genome.

scholarly journals Centromeres under Pressure: Evolutionary Innovation in Conflict with Conserved Function

Genes ◽  
2020 ◽  
Vol 11 (8) ◽  
pp. 912 ◽  
Author(s):  
Elisa Balzano ◽  
Simona Giunta
Keyword(s):  
Genome Instability ◽  
Dynamic Features ◽  
Sequence Composition ◽  
Evolutionary Innovation ◽  
Microtubule Attachment ◽  
Meiotic Transmission ◽  
Secondary Dna Structures ◽  
Dna 2 ◽  
And Function ◽  
Mitosis And Meiosis

Centromeres are essential genetic elements that enable spindle microtubule attachment for chromosome segregation during mitosis and meiosis. While this function is preserved across species, centromeres display an array of dynamic features, including: (1) rapidly evolving DNA; (2) wide evolutionary diversity in size, shape and organization; (3) evidence of mutational processes to generate homogenized repetitive arrays that characterize centromeres in several species; (4) tolerance to changes in position, as in the case of neocentromeres; and (5) intrinsic fragility derived by sequence composition and secondary DNA structures. Centromere drive underlies rapid centromere DNA evolution due to the “selfish” pursuit to bias meiotic transmission and promote the propagation of stronger centromeres. Yet, the origins of other dynamic features of centromeres remain unclear. Here, we review our current understanding of centromere evolution and plasticity. We also detail the mutagenic processes proposed to shape the divergent genetic nature of centromeres. Changes to centromeres are not simply evolutionary relics, but ongoing shifts that on one side promote centromere flexibility, but on the other can undermine centromere integrity and function with potential pathological implications such as genome instability.

scholarly journals Chromatin Domain Organization of the TCRb Locus and Its Perturbation by Ectopic CTCF Binding

2017 ◽  
Vol 37 (9) ◽  
Author(s):  
Pratishtha Rawat ◽  
Manisha Jalan ◽  
Ananya Sadhu ◽  
Abhilasha Kanaujia ◽  
Madhulika Srivastava
Keyword(s):  
Long Range ◽  
Ctcf Binding ◽  
Spatial Proximity ◽  
Chromatin Domain ◽  
Regulation Of Transcription ◽  
Chromatin Loop ◽  
Vdj Recombination ◽  
Chromatin Loops ◽  
Chromatin Interactions ◽  
Tcrb Locus

ABSTRACT CTCF-mediated chromatin interactions influence organization and function of mammalian genome in diverse ways. We analyzed the interactions among CTCF binding sites (CBS) at the murine TCRb locus to discern the role of CTCF-mediated interactions in the regulation of transcription and VDJ recombination. Chromosome conformation capture analysis revealed thymocyte-specific long-range intrachromosomal interactions among various CBS across the locus that were relevant for defining the limit of the enhancer Eb-regulated recombination center (RC) and for facilitating the spatial proximity of TCRb variable (V) gene segments to the RC. Ectopic CTCF binding in the RC region, effected via genetic manipulation, altered CBS-directed chromatin loops, interfered with RC establishment, and reduced the spatial proximity of the RC with Trbv segments. Changes in chromatin loop organization by ectopic CTCF binding were relatively modest but influenced transcription and VDJ recombination dramatically. Besides revealing the importance of CTCF-mediated chromatin organization for TCRb regulation, the observed chromatin loops were consistent with the emerging idea that CBS orientations influence chromatin loop organization and underscored the importance of CBS orientations for defining chromatin architecture that supports VDJ recombination. Further, our study suggests that in addition to mediating long-range chromatin interactions, CTCF influences intricate configuration of chromatin loops that govern functional interactions between elements.

scholarly journals Large domains of heterochromatin direct the formation of short mitotic chromosome loops

2020 ◽  
Author(s):  
Maximilian H. Fitz-James ◽  
Pin Tong ◽  
Alison L. Pidoux ◽  
Hakan Ozadam ◽  
Liyan Yang ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Dna Sequence ◽  
Mitotic Chromosome ◽  
Chromatin Loop ◽  
Mitotic Chromosomes ◽  
Chromatin Compaction ◽  
Chromatin Loops ◽  
Distinct Structure ◽  
Central Protein ◽  
Chromatin Proteins

AbstractDuring mitosis chromosomes reorganise into highly compact, rod-shaped forms, thought to consist of consecutive chromatin loops around a central protein scaffold. Condensin complexes are involved in chromatin compaction, but the contribution of other chromatin proteins, DNA sequence and histone modifications is less understood. A large region of fission yeast DNA inserted into a mouse chromosome was previously observed to adopt a mitotic organisation distinct from that of surrounding mouse DNA. Here we show that a similar distinct structure is common to a large subset of insertion events in both mouse and human cells and is coincident with the presence of high levels of heterochromatic H3 lysine 9 trimethylation (H3K9me3). Hi-C and microscopy indicate that the heterochromatinised fission yeast DNA is organised into smaller chromatin loops than flanking euchromatic mouse chromatin. We conclude that heterochromatin alters chromatin loop size, thus contributing to the distinct appearance of heterochromatin on mitotic chromosomes, such as at centromeres.

Smc3 acetylation, Pds5 and Scc2 control the translocase activity that establishes cohesin dependent chromatin loops

2021 ◽  
Author(s):  
Nathalie Bastié ◽  
Christophe Chapard ◽  
Lise Dauban ◽  
Olivier Gadal ◽  
Frederic Beckouёt ◽  
...  
Keyword(s):  
Spatial Organization ◽  
Living Cells ◽  
S Phase ◽  
Dependent Manner ◽  
Chromatin Loop ◽  
Dna Loops ◽  
Chromatin Loops ◽  
Loop Expansion ◽  
Dna Loop ◽  
Recombination Processes

ABSTRACTChromosome spatial organization and dynamics influence DNA-related metabolic processes. SMC complexes like cohesin are essential instruments of chromosome folding. Cohesin-dependent chromatin loops bring together distal loci to regulate gene transcription, DNA repair and V(D)J recombination processes. Here we characterize further the roles of members of the cohesin holocomplex in regulating chromatin loop expansion, showing that Scc2, which stimulates cohesin ATPase activity, is essential for the translocation process required to extend DNA loop length. Eco1-dependent acetylation of Smc3 during S phase counteracts this activity through the stabilization of Pds5, to finely tune loop sizes and stability during G2. Inhibiting Pds5 in G2 leads to a strong enlargement of pre-established, stable DNA loops, in a Scc2-dependent manner. Altogether, the study strongly supports a Scc2-mediated translocation process driving expansion of DNA loops in living cells.

scholarly journals Reproducibility of SNV-calling in multiple sequencing runs from single tumors

PeerJ ◽  
2016 ◽  
Vol 4 ◽  
pp. e1508 ◽  
Author(s):  
Dakota Z. Derryberry ◽  
Matthew C. Cowperthwaite ◽  
Claus O. Wilke
Keyword(s):  
Glioblastoma Multiforme ◽  
Large Fraction ◽  
Point Mutations ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Single Nucleotide Variants ◽  
Specific Point ◽  
Single Nucleotide ◽  
Cancer Genome Atlas ◽  
Genome Atlas

We examined 55 technical sequencing replicates of Glioblastoma multiforme (GBM) tumors from The Cancer Genome Atlas (TCGA) to ascertain the degree of repeatability in calling single-nucleotide variants (SNVs). We used the same mutation-calling pipeline on all pairs of samples, and we measured the extent of the overlap between two replicates; that is, how many specific point mutations were found in both replicates. We further tested whether additional filtering increased or decreased the size of the overlap. We found that about half of the putative mutations identified in one sequencing run of a given sample were also identified in the second, and that this percentage remained steady throughout orders of magnitude of variation in the total number of mutations identified (from 23 to 10,966). We further found that using filtering after SNV-calling removed the overlap completely. We concluded that there is variation in the frequency of mutations in GBMs, and that while some filtering approaches preferentially removed putative mutations found in only one replicate, others removed a large fraction of putative mutations found in both.

scholarly journals Systematic Evaluation of DNA Sequence Variations on in vivo Transcription Factor Binding Affinity

2021 ◽  
Vol 12 ◽  
Author(s):  
Yutong Jin ◽  
Jiahui Jiang ◽  
Ruixuan Wang ◽  
Zhaohui S. Qin
Keyword(s):  
Transcription Factor ◽  
Binding Affinity ◽  
Binding Sites ◽  
Association Studies ◽  
Systematic Evaluation ◽  
Binding Motif ◽  
Genome Wide Association Studies ◽  
Single Nucleotide Variants ◽  
Protein Coding

The majority of the single nucleotide variants (SNVs) identified by genome-wide association studies (GWAS) fall outside of the protein-coding regions. Elucidating the functional implications of these variants has been a major challenge. A possible mechanism for functional non-coding variants is that they disrupted the canonical transcription factor (TF) binding sites that affect the in vivo binding of the TF. However, their impact varies since many positions within a TF binding motif are not well conserved. Therefore, simply annotating all variants located in putative TF binding sites may overestimate the functional impact of these SNVs. We conducted a comprehensive survey to study the effect of SNVs on the TF binding affinity. A sequence-based machine learning method was used to estimate the change in binding affinity for each SNV located inside a putative motif site. From the results obtained on 18 TF binding motifs, we found that there is a substantial variation in terms of a SNV’s impact on TF binding affinity. We found that only about 20% of SNVs located inside putative TF binding sites would likely to have significant impact on the TF-DNA binding.

scholarly journals The effects of sequence length and composition of random sequence peptides on the growth of E. coli cells

2021 ◽  
Author(s):  
Johana R. C. Fajardo ◽  
Diethard Tautz
Keyword(s):  
Cell Growth ◽  
De Novo ◽  
Random Sequence ◽  
Large Fraction ◽  
Gc Content ◽  
Sequence Length ◽  
E Coli ◽  
Aggregation Propensity ◽  
Evolutionary Innovation ◽  
Frequency Changes

We study the potential for the de novo evolution of genes from random nucleotide sequences using libraries of E. coli expressing random sequence peptides. We assess the effects of such peptides on cell growth by monitoring frequency changes of individual clones in a complex library through four serial passages. Using a new analysis pipeline that allows to trace peptides of all lengths, we find that over half of the peptides have consistent effects on cell growth. Across nine different experiments, around 16 % of clones increase in frequency and 36 % decrease, with some variation between individual experiments. Shorter peptides (8 - 20 residues), are more likely to increase in frequency, longer ones are more likely to decrease. GC content, amino acid composition, intrinsic dis-order and aggregation propensity show slightly different patterns between peptide groups. Sequences that increase in frequency tend to be more disordered with lower aggregation propensity. This coincides with the observation that young genes with more disordered structures are better tolerated in genomes. Our data indicate that random sequences can be a source of evolutionary innovation, since a large fraction of them are well tolerated by the cells or can provide a growth advantage.

scholarly journals Phylogenomics and population genomics of SARS-CoV-2 in Mexico reveals variants of interest (VOI) and a mutation in the Nucleocapsid protein associated with symptomatic versus asymptomatic carriers

2021 ◽  
Author(s):  
Francisco Barona-Gomez ◽  
Luis Delaye ◽  
Erik Diaz-Valenzuela ◽  
Fabien Plisson ◽  
Arely Cruz-Perez ◽  
...  
Keyword(s):  
Nucleocapsid Protein ◽  
Population Genomics ◽  
Bimodal Distribution ◽  
Central Mexico ◽  
Binding Motif ◽  
Single Nucleotide Variants ◽  
Nucleocapsid Proteins ◽  
Asymptomatic Carriers ◽  
Genetic Patterns

Understanding the evolution of SARS-CoV-2 virus in various regions of the world during the Covid19 pandemic is of the utmost importance to help mitigate the effects of this devastating disease. We describe the phylogenomic and population genetic patterns of the virus in Mexico during the pre-vaccination stage, including asymptomatic carriers. Our RT-qPCR screening and phylogenomics directed a sequence/structure analysis of the Spike glycoprotein, revealing mutation of concern E484K in genomes from central Mexico, in addition to the nationwide prevalence of the imported variant 20C/S:452R (B.1.427/9). Overall, the detected variants in Mexico show mutations in the N-terminal domain (i.e., R190M), in the receptor-binding motif (i.e., T478K, E484K), within the S1-S2 subdomains (i.e., P681R/H, T732A), and at the basis of the protein, V1176F, raising concerns about the lack of phenotypic and clinical data available for the postulated variants of interest (VOIs) 20B/478K.V1 and P.3. Moreover, the population patterns of Single Nucleotide Variants (SNVs) from symptomatic and asymptomatic carriers sampled with a self-sampling scheme, revealed a bimodal distribution of polymorphisms in all three sampled localities from central Mexico, and confirmed the presence of several fixed variants, mostly from the 241T-3037T-14408T-23403G haplotype common in Asia. Despite gene flow among Mexican localities, we found differences in both the allelic frequencies among localities and the allelic imbalance of the mutation S194L of the nucleocapsid protein between symptomatic and asymptomatic carriers. Our results highlight the dual role of Spike and Nucleocapsid proteins in adaptive evolution of SARS-CoV-2 to their hosts and provide a baseline for specific follow-up of mutations of concern during the vaccination stage in Mexico.

Sign in / Sign up

Export Citation Format

Share Document