scholarly journals Comprehensive analysis of epigenetic signatures of human transcription control†

2020 ◽  
Author(s):  
Guillaume Devailly ◽  
Anagha Joshi
Keyword(s):  
Transcription Termination ◽  
Epigenetic Modifications ◽  
Comprehensive Analysis ◽  
Transcription Control ◽  
Transcription Start Sites ◽  
Sequencing Technologies ◽  
Transcription Profiles ◽  
A Genome ◽  
Hypotheses Generation ◽  
Epigenetic Signatures

Advances in sequencing technologies have enabled exploration of epigenetic and transcription profiles at a genome-wide level. The epigenetic and transcriptional landscape is now available in hundreds of mammalian cell and tissue contexts. Many studies have performed multi-omics analyses using these datasets to enhance our understanding of relationships between epigenetic modifications and transcription regulation. Nevertheless, most studies so far have focused on the promoters/enhancers and transcription start sites, and other features of transcription control including exons, introns and transcription termination remain under explored. We investigated interplay between epigenetic modifications and diverse transcription features using the data generated by the Roadmap Epigenomics project. A comprehensive analysis of histone modifications, DNA methylation, and RNA-seq data of about thirty human cell lines and tissue types, allowed us to confirm the generality of previously described relations, as well as to generate new hypotheses about the interplay between epigenetic modifications and transcript features. Importantly, our analysis included previously under-explored features of transcription control namely, transcription termination sites, exon-intron boundaries, middle exons and exon inclusion ratio. We have made the analyses freely available to the scientific community at joshiapps.cbu.uib.no/perepigenomics_app/ for easy exploration, validation and hypotheses generation.

scholarly journals Comprehensive analysis of epigenetic signatures of mammalian transcription control

2021 ◽  
Author(s):  
Guillaume Devailly ◽  
Anagha Joshi
Keyword(s):  
Mammalian Cell ◽  
Comprehensive Analysis ◽  
Transcription Control ◽  
Sequencing Technologies ◽  
Transcription Profiles ◽  
Genome Wide ◽  
A Genome ◽  
Epigenetic Signatures ◽  
Transcriptional Landscape

Advances in sequencing technologies have enabled exploration of epigenetic and transcription profiles at a genome-wide level. Epigenetic and transcriptional landscape is now available across hundreds of mammalian cell and tissue...

scholarly journals Topoisomerase IIβ targets DNA crossovers formed between distant homologous sites to modulate chromatin structure and gene expression

2018 ◽  
Author(s):  
Mary Miyaji ◽  
Ryohei Furuta ◽  
Osamu Hosoya ◽  
Kuniaki Sano ◽  
Norikazu Hara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gene Regulation ◽  
Model Building ◽  
Mapping Technique ◽  
Dna Duplexes ◽  
Transcription Start Sites ◽  
A Genome ◽  
Topo Ii ◽  
Type Ii Dna Topoisomerases ◽  
Strand Passage

AbstractBackgroundType II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T-segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be placed far from each other on the same chromosome. However, no direct evidence for this to occur has been described so far due to lack of proper methodology.ResultsThe beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. To elucidate the enzyme’s role in the process, here we devise a genome-wide mapping technique for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It became clear that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that the DSP sites are intertwined or knotted and topo IIβ is engaged in unknotting reaction that leads to chromatin decondensation and gene regulation.ConclusionsWhen combined with categorized gene expression analysis, the model-based prediction of DSP sites reveals that DSP is one of the key factors for topo IIβ-dependency of neuronal gene regulation.

scholarly journals DNA methylation marks inter-nucleosome linker regions throughout the human genome

2013 ◽  
Author(s):  
Benjamin P. Berman ◽  
Yaping Liu ◽  
Theresa K. Kelly
Keyword(s):  
Dna Methylation ◽  
Human Genome ◽  
Ctcf Binding ◽  
Gene Promoters ◽  
Cpg Dinucleotides ◽  
Sequencing Technologies ◽  
Nucleosome Organization ◽  
Genome Wide ◽  
A Genome ◽  
Sequencing Studies

Background: Nucleosome organization and DNA methylation are two mechanisms that are important for proper control of mammalian transcription, as well as epigenetic dysregulation associated with cancer. Whole-genome DNA methylation sequencing studies have found that methylation levels in the human genome show periodicities of approximately 190 bp, suggesting a genome-wide relationship between the two marks. A recent report (Chodavarapu et al., 2010) attributed this to higher methylation levels of DNA within nucleosomes. Here, we analyzed a number of published datasets and found a more compelling alternative explanation, namely that methylation levels are highest in linker regions between nucleosomes. Results: Reanalyzing the data from (Chodavarapu et al., 2010), we found that nucleosome-associated methylation could be strongly confounded by known sequence-related biases of the next-generation sequencing technologies. By accounting for these biases and using an unrelated nucleosome profiling technology, NOMe-seq, we found that genome-wide methylation was actually highest within linker regions occurring between nucleosomes in multi-nucleosome arrays. This effect was consistent among several methylation datasets generated independently using two unrelated methylation assays. Linker-associated methylation was most prominent within long Partially Methylated Domains (PMDs) and the positioned nucleosomes that flank CTCF binding sites. CTCF adjacent nucleosomes retained the correct positioning in regions completely devoid of CpG dinucleotides, suggesting that DNA methylation is not required for proper nucleosomes positioning. Conclusions: The biological mechanisms responsible for DNA methylation patterns outside of gene promoters remain poorly understood. We identified a significant genome-wide relationship between nucleosome organization and DNA methylation, which can be used to more accurately analyze and understand the epigenetic changes that accompany cancer and other diseases.

scholarly journals DNA methylation enables transposable element-driven genome expansion

2020 ◽  
Vol 117 (32) ◽  
pp. 19359-19366
Author(s):  
Wanding Zhou ◽  
Gangning Liang ◽  
Peter L. Molloy ◽  
Peter A. Jones
Keyword(s):  
Cytosine Methylation ◽  
Host Genome ◽  
Substantial Part ◽  
Gene Control ◽  
Cytosine Deamination ◽  
Transcription Start Sites ◽  
Genome Expansion ◽  
A Genome ◽  
Cpg Dinucleotide ◽  
Regulatory Functions

Multicellular eukaryotic genomes show enormous differences in size. A substantial part of this variation is due to the presence of transposable elements (TEs). They contribute significantly to a cell’s mass of DNA and have the potential to become involved in host gene control. We argue that the suppression of their activities by methylation of the C–phosphate–G (CpG) dinucleotide in DNA is essential for their long-term accommodation in the host genome and, therefore, to its expansion. An inevitable consequence of cytosine methylation is an increase in C-to-T transition mutations via deamination, which causes CpG loss. Cytosine deamination is often needed for TEs to take on regulatory functions in the host genome. Our study of the whole-genome sequences of 53 organisms showed a positive correlation between the size of a genome and the percentage of TEs it contains, as well as a negative correlation between size and the CpG observed/expected (O/E) ratio in both TEs and the host DNA. TEs are seldom found at promoters and transcription start sites, but they are found more at enhancers, particularly after they have accumulated C-to-T and other mutations. Therefore, the methylation of TE DNA allows for genome expansion and also leads to new opportunities for gene control by TE-based regulatory sites.

scholarly journals Towards population genomics in non-model species with large genomes: a case study of the marine zooplankton Calanus finmarchicus

2019 ◽  
Vol 6 (2) ◽  
pp. 180608 ◽  
Author(s):  
Marvin Choquet ◽  
Irina Smolina ◽  
Anusha K. S. Dhanasiri ◽  
Leocadio Blanco-Bercial ◽  
Martina Kopp ◽  
...  
Keyword(s):  
Population Genomics ◽  
Single Copy ◽  
Calanus Finmarchicus ◽  
Model Species ◽  
Reduced Representation ◽  
Marine Copepod ◽  
Marine Zooplankton ◽  
Sequencing Technologies ◽  
A Genome ◽  
Large Genomes

Advances in next-generation sequencing technologies and the development of genome-reduced representation protocols have opened the way to genome-wide population studies in non-model species. However, species with large genomes remain challenging, hampering the development of genomic resources for a number of taxa including marine arthropods. Here, we developed a genome-reduced representation method for the ecologically important marine copepod Calanus finmarchicus (haploid genome size of 6.34 Gbp). We optimized a capture enrichment-based protocol based on 2656 single-copy genes, yielding a total of 154 087 high-quality SNPs in C. finmarchicus including 62 372 in common among the three locations tested. The set of capture probes was also successfully applied to the congeneric C. glacialis . Preliminary analyses of these markers revealed similar levels of genetic diversity between the two Calanus species, while populations of C. glacialis showed stronger genetic structure compared to C. finmarchicus . Using this powerful set of markers, we did not detect any evidence of hybridization between C. finmarchicus and C. glacialis . Finally, we propose a shortened version of our protocol, offering a promising solution for population genomics studies in non-model species with large genomes.

scholarly journals How to use new biology to guide therapy in multiple myeloma

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 342-349 ◽  
Author(s):  
Gareth J. Morgan ◽  
Martin F. Kaiser
Keyword(s):  
Multiple Myeloma ◽  
Molecular Mechanisms ◽  
Developmental Stages ◽  
Survival Rates ◽  
Current Treatment ◽  
Next Generation ◽  
Molecular Subgroups ◽  
Treatment Protocols ◽  
Sequencing Technologies ◽  
A Genome

Abstract Recent advances in multiple myeloma (MM) therapy have led to significantly longer median survival rates and some patients being cured. At the same time, our understanding of MM biology and the molecular mechanisms driving the disease is constantly improving. Next-generation sequencing technologies now allow insights into the genetic aberrations in MM at a genome-wide scale and across different developmental stages in the course of an individual tumor. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed. The potential of targeted next-generation diagnostic tests to rapidly identify clinically relevant molecular subgroups is being evaluated. The technical tools to detect and define tumor subclones may potentially become clinically relevant because intraclonal tumor heterogeneity has become apparent in many cancers. The emergence of different MM subclones under the selective pressure of treatment is important in MM, especially in the context of maintenance therapy and treatment for asymptomatic stages of the disease. Finally, novel diagnostic and therapeutic achievements have to be implemented into innovative clinical trial strategies with smaller trials for molecularly defined high-risk patients and large trials with a long follow-up for the patients most profiting from the current treatment protocols. These combined approaches will hopefully transform the current one-for-all care into a more tailored, individual therapeutic strategy for MM patients.

Integrative Analysis Reveals Multiple Alterations of p53 Signaling Pathway Components In Primary Diffuse Large B-Cell Lymphomas

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 635-635
Author(s):  
Bjoern Chapuy ◽  
Stefano Monti ◽  
Kunihiko Takeyama ◽  
Gad Getz ◽  
Scott J Rodig ◽  
...  
Keyword(s):  
B Cell ◽  
Copy Number ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Comprehensive Analysis ◽  
Multiple Hypothesis Testing ◽  
E3 Ligases ◽  
P53 Signaling ◽  
A Genome ◽  
Large B Cell

Abstract Abstract 635 Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease with infrequent alterations of multiple apoptotic, developmental and signaling pathways. Inactivating somatic mutations of the p53 tumor suppressor are uncommon in DLBCL, prompting speculation regarding alternative mechanisms of modulating p53 activity in this disease. As part of a comprehensive analysis of genetic alterations in DLBCL, we recently integrated high-resolution copy number data and transcription profiles in a series of 81 newly diagnosed previously untreated DLBCLs. Copy number (CN) alterations were evaluated using Affymetrix SNP Array 6.0 data on over 1.8 million genomic loci (906,000 SNP probe sets and 946,000 copy number probes) and a data-processing pipeline incorporating the normalization, calibration, and segmentation of the CN profiles and their analysis by the GISTIC algorithm. The genes within the peak and region of each GISTIC-identified alteration were tested for association with the corresponding transcripts' expression and significance values were corrected for multiple hypothesis testing by the false discovery rate (FDR) procedure, with the correction accounting for both the multiple genes within each peak and the multiple peaks. The signature for a given copy number alteration was then defined as the set of within-peak and -region transcripts with FDR q-values < 0.25. The alteration signatures thus defined were then tested for pathway/gene set enrichment based on the hypergeometric distribution, using a compendium of gene sets from the MSigDB repository (Broad Institute). This analysis highlighted a genome-wide pattern whereby: i) individual pathways are targeted by multiple alterations at different loci (with different genes of the same pathway located within distinct CN alteration peaks or regions); and ii) members of multiple pathways are targeted by the same alteration (with genes co-located within a single CN alteration belonging to different pathways). The most highly significant enriched pathways (FDR < .05) included apoptotic, p53 signaling, and ARF pathways and identified multiple modulators and effectors of normal p53 activity. These include: deletion of the MDM2-inhibitor, ARF; amplification of the p53 E3 ligases, MDM2 and COP1; deletion of p53 itself; deletion of the ribosomal protein that enhances p53 translation following DNA damage, RPL26; and deletion of p53 effectors including BNIP3L and DFFB. Of note, the deletion of 17p13.1 encompasses both p53 and its positive modulator, RPL26. In all cases, the observed alterations in p53 pathway components would decrease functionally active p53 protein and p53 apoptotic effectors in primary DLBCLs. Taken together, these data identify alternative genetic mechanisms for reducing p53 activity in DLBCL and highlight the value of an integrated comprehensive analysis of genetic alterations in this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Gammaherpesvirus Lytic Gene Expression as Characterized by DNA Array

2002 ◽  
Vol 76 (12) ◽  
pp. 6244-6256 ◽  
Author(s):  
Joo Wook Ahn ◽  
Kenneth L. Powell ◽  
Paul Kellam ◽  
Dagmar G. Alber
Keyword(s):  
Gene Expression ◽  
De Novo ◽  
Expression Profiles ◽  
Cdna Array ◽  
Gene Expression Profiles ◽  
Hierarchical Cluster ◽  
Murine Gammaherpesvirus ◽  
Transcription Profiles ◽  
A Genome

ABSTRACT Gammaherpesviruses are associated with a number of diseases including lymphomas and other malignancies. Murine gammaherpesvirus 68 (MHV-68) constitutes the most amenable animal model for this family of pathogens. However experimental characterization of gammaherpesvirus gene expression, at either the protein or RNA level, lags behind that of other, better-studied alpha- and beta-herpesviruses. We have developed a cDNA array to globally characterize MHV-68 gene expression profiles, thus providing an experimental supplement to a genome that is chiefly annotated by homology. Viral genes started to be transcribed as early as 3 h postinfection (p.i.), and this was followed by a rapid escalation of gene expression that could be seen at 5 h p.i. Individual genes showed their own transcription profiles, and most genes were still being expressed at 18 h p.i. Open reading frames (ORFs) M3 (chemokine-binding protein), 52, and M9 (capsid protein) were particularly noticeable due to their very high levels of expression. Hierarchical cluster analysis of transcription profiles revealed four main groups of genes and allowed functional predictions to be made by comparing expression profiles of uncharacterized genes to those of genes of known function. Each gene was also categorized according to kinetic class by blocking de novo protein synthesis and viral DNA replication in vitro. One gene, ORF 73, was found to be expressed with α-kinetics, 30 genes were found to be expressed with β-kinetics, and 42 genes were found to be expressed with γ-kinetics. This fundamental characterization furthers the development of this model and provides an experimental basis for continued investigation of gammaherpesvirus pathology.

scholarly journals Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

2016 ◽  
Vol 2 (6) ◽  
pp. e1501678 ◽  
Author(s):  
Till F. M. Andlauer ◽  
Dorothea Buck ◽  
Gisela Antony ◽  
Antonios Bayas ◽  
Lukas Bechmann ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genome Wide Association Study ◽  
Immune Cell ◽  
Susceptibility Loci ◽  
Genome Wide ◽  
A Genome ◽  
Genetic Substructure ◽  
Epigenetic Signatures ◽  
Folate Cycle ◽  
Ms Pathogenesis

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genesL3MBTL3,MAZ,ERG, andSHMT1. The lead variant atSHMT1was replicated in an independent Sardinian cohort. Products of the genesL3MBTL3,MAZ, andERGplay important roles in immune cell regulation.SHMT1encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

scholarly journals The first decade of estrogen receptor cistromics in breast cancer

2016 ◽  
Vol 229 (2) ◽  
pp. R43-R56 ◽  
Author(s):  
Koen D Flach ◽  
Wilbert Zwart
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Transcription Factor ◽  
Tiling Array ◽  
Estrogen Receptor Α ◽  
Sequencing Technologies ◽  
Hormone Receptor Positive ◽  
Genome Wide ◽  
A Genome ◽  
On Chip

The advent of genome-wide transcription factor profiling has revolutionized the field of breast cancer research. Estrogen receptor α (ERα), the major drug target in hormone receptor-positive breast cancer, has been known as a key transcriptional regulator in tumor progression for over 30 years. Even though this function of ERα is heavily exploited and widely accepted as an Achilles heel for hormonal breast cancer, only since the last decade we have been able to understand how this transcription factor is functioning on a genome-wide scale. Initial ChIP-on-chip (chromatin immunoprecipitation coupled with tiling array) analyses have taught us that ERα is an enhancer-associated factor binding to many thousands of sites throughout the human genome and revealed the identity of a number of directly interacting transcription factors that are essential for ERα action. More recently, with the development of massive parallel sequencing technologies and refinements thereof in sample processing, a genome-wide interrogation of ERα has become feasible and affordable with unprecedented data quality and richness. These studies have revealed numerous additional biological insights into ERα behavior in cell lines and especially in clinical specimens. Therefore, what have we actually learned during this first decade of cistromics in breast cancer and where may future developments in the field take us?

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