scholarly journals Epigenetics of Ancient DNA

Acta Naturae ◽  
2016 ◽  
Vol 8 (3) ◽  
pp. 72-76 ◽  
Author(s):  
S. V. Zhenilo ◽  
A. S. Sokolov ◽  
E. B. Prokhortchou
Keyword(s):  
Ancient Dna ◽  
Methylation Status ◽  
Regulation Of Gene Expression ◽  
Genetic Selection ◽  
Regulatory Elements ◽  
Transcription Start Sites ◽  
Genome Wide ◽  
Evolutionary Changes ◽  
Hoxd Cluster ◽  
Different Populations

Initially, the study of DNA isolated from ancient specimens had been based on the analysis of the primary nucleotide sequence. This approach has allowed researchers to study the evolutionary changes that occur in different populations and determine the influence of the environment on genetic selection. However, the improvement of methodological approaches to genome-wide analysis has opened up new possibilities in the search for the epigenetic mechanisms involved in the regulation of gene expression. It was discovered recently that the methylation status of the regulatory elements of the HOXD cluster and MEIS1 gene changed during human evolution. Epigenetic changes in these genes played a key role in the evolution of the limbs of modern humans. Recent works have demonstrated that it is possible to determine the transcriptional activity of genes in ancient DNA samples by combining information on DNA methylation and the DNAaseI hypersensitive sequences located at the transcription start sites of genes. In the nearest future, if a preserved fossils brain is found, it will be possible to identify the evolutionary changes in the higher nervous system associated with epigenetic differences.

scholarly journals Genetic and Epigenetic Fine Mapping of Complex Trait Associated Loci in the Human Liver

2018 ◽  
Author(s):  
Minal Çalışkan ◽  
Elisabetta Manduchi ◽  
H. Shanker Rao ◽  
Julian A Segert ◽  
Marcia Holsbach Beltrame ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genetic Variation ◽  
Histone Modification ◽  
Human Liver ◽  
Complex Disease ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Chromatin Interaction ◽  
Genome Wide ◽  
The Impact

ABSTRACTDeciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

scholarly journals Graph-based data integration predicts long-range regulatory interactions across the human genome

2014 ◽  
Author(s):  
Sofie Demeyer ◽  
Tom Michoel
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Regulation Of Gene Expression ◽  
Cell Types ◽  
Exon Array ◽  
Regulatory Elements ◽  
Computational Method ◽  
Open Chromatin ◽  
Transcription Start Sites ◽  
Distal Regulatory Elements

Transcriptional regulation of gene expression is one of the main processes that affect cell diversification from a single set of genes. Regulatory proteins often interact with DNA regions located distally from the transcription start sites (TSS) of the genes. We developed a computational method that combines open chromatin and gene expression information for a large number of cell types to identify these distal regulatory elements. Our method builds correlation graphs for publicly available DNase-seq and exon array datasets with matching samples and uses graph-based methods to filter findings supported by multiple datasets and remove indirect interactions. The resulting set of interactions was validated with both anecdotal information of known long-range interactions and unbiased experimental data deduced from Hi-C and CAGE experiments. Our results provide a novel set of high-confidence candidate open chromatin regions involved in gene regulation, often located several Mb away from the TSS of their target gene.

scholarly journals AP-TSS: A New Method for the Analysis of RNA Expression from Particular and Challenging Transcription Start Sites

Biomolecules ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 827
Author(s):  
Gabriel Le Berre ◽  
Virginie Hossard ◽  
Jean-Francois Riou ◽  
Anne-Laure Guieysse-Peugeot
Keyword(s):  
Rna Polymerase Iii ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Alternative Promoter ◽  
Regulation Of Transcription ◽  
Transcription Start ◽  
Transcription Start Sites ◽  
Non Coding Rna ◽  
Methylation Inhibitor ◽  
Global Increase

Alternative promoter usage involved in the regulation of transcription, splicing, and translation contributes to proteome diversity and is involved in a large number of diseases, in particular, cancer. Epigenetic mechanisms and cis regulatory elements are involved in alternative promoter activity. Multiple transcript isoforms can be produced from a gene, due to the initiation of transcription at different transcription start sites (TSS). These transcripts may not have regions that allow discrimination during RT-qPCR, making quantification technically challenging. This study presents a general method for the relative quantification of a transcript synthesized from a particular TSS that we called AP-TSS (analysis of particular TSS). AP-TSS is based on the specific elongation of the cDNA of interest, followed by its quantification by qPCR. As proof of principle, AP-TSS was applied to two non-coding RNA: telomeric repeat-containing RNAs (TERRA) from a particular subtelomeric TSS, and Alu transcripts. The treatment of cells with a DNA methylation inhibitor was associated with a global increase of the total TERRA level, but the TERRA expression from the TSS of interest did not change in HT1080 cells, and only modestly increased in HeLa cells. This result suggests that TERRA upregulation induced by global demethylation of the genome is mainly due to activation from sites other than this particular TSS. For Alu RNA, the signal obtained by AP-TSS is specific for the RNA Polymerase III-dependent Alu transcript. In summary, our method provides a tool to study regulation of gene expression from a given transcription start site, in different conditions that could be applied to many genes. In particular, AP-TSS can be used to investigate the epigenetic regulation of alternative TSS usage that is of importance for the development of epigenetic-targeted therapies.

scholarly journals Developing a Riboswitch-Mediated Regulatory System for Metabolic Flux Control in Thermophilic Bacillus methanolicus

2021 ◽  
Vol 22 (9) ◽  
pp. 4686
Author(s):  
Marta Irla ◽  
Sigrid Hakvåg ◽  
Trygve Brautaset
Keyword(s):  
Gene Expression ◽  
Metabolic Flux ◽  
Regulation Of Gene Expression ◽  
Regulatory System ◽  
Regulatory Elements ◽  
Rna Seq ◽  
Transcription Start Sites ◽  
Bacillus Methanolicus ◽  
Purine Riboswitch ◽  
And Control

Genome-wide transcriptomic data obtained in RNA-seq experiments can serve as a reliable source for identification of novel regulatory elements such as riboswitches and promoters. Riboswitches are parts of the 5′ untranslated region of mRNA molecules that can specifically bind various metabolites and control gene expression. For that reason, they have become an attractive tool for engineering biological systems, especially for the regulation of metabolic fluxes in industrial microorganisms. Promoters in the genomes of prokaryotes are located upstream of transcription start sites and their sequences are easily identifiable based on the primary transcriptome data. Bacillus methanolicus MGA3 is a candidate for use as an industrial workhorse in methanol-based bioprocesses and its metabolism has been studied in systems biology approaches in recent years, including transcriptome characterization through RNA-seq. Here, we identify a putative lysine riboswitch in B. methanolicus, and test and characterize it. We also select and experimentally verify 10 putative B. methanolicus-derived promoters differing in their predicted strength and present their functionality in combination with the lysine riboswitch. We further explore the potential of a B. subtilis-derived purine riboswitch for regulation of gene expression in the thermophilic B. methanolicus, establishing a novel tool for inducible gene expression in this bacterium.

scholarly journals Divergently Transcribed ncRNAs in Escherichia coli: Refinement of the Transcription Starts Assumes Functional Diversification

2021 ◽  
Vol 8 ◽  
Author(s):  
Sergey Kiselev ◽  
Natalia Markelova ◽  
Irina Masulis
Keyword(s):  
Escherichia Coli ◽  
Regulation Of Gene Expression ◽  
Regulatory Elements ◽  
Progressive Increase ◽  
Biological Molecules ◽  
Functional Diversification ◽  
Transcription Start Sites ◽  
Intergenic Regions ◽  
Regulatory Rnas ◽  
Exact Positions

Non-coding regulatory RNAs (ncRNAs) comprise specialized group of essential genetically encoded biological molecules involved in the wide variety of cellular metabolic processes. The progressive increase in the number of newly identified ncRNAs and the defining of their genome location indicate their predominant nesting in intergenic regions and expression under the control of their own regulatory elements. At the same time, the regulation of ncRNA’s transcription cannot be considered in isolation from the processes occurring in the immediate genetic environment. A number of experimental data indicate the notable impact of positional regulation of gene expression mediated by dynamic temporal DNA rearrangements accompanying transcription events in the vicinity of neighboring genes. This issue can be perceived as particularly significant for divergently transcribed ncRNAs being actually subjected to double regulatory pressure. Based on available results of RNAseq experiments for Escherichia coli, we screened out divergent ncRNAs and the adjacent genes for the exact positions of transcription start sites (TSSs) and relative efficiency of RNA production. This analysis revealed extension or shortening of some previously annotated ncRNAs resulting in modified secondary structure, confirmed stable expression of four ncRNAs annotated earlier as putative, and approved the possibility of expression of divergently transcribed ncRNAs containing repetitive extragenic palindromic (REP) elements. The biogenesis of secreted ncRNAs from divergently transcribed ffs, chiX, ralA, and ryhB is discussed taking into account positions of TSSs. Refinement of TSSs for the neighboring genes renders some ncRNAs as true antisense overlapping with 5′UTR of divergently transcribed mRNAs.

scholarly journals Systematic comparison of experimental assays and analytical pipelines for identification of active enhancers genome-wide

2021 ◽  
Author(s):  
Li Yao ◽  
Jin Liang ◽  
Abdullah Ozer ◽  
Alden King-Yung Leung ◽  
John T. Lis ◽  
...  
Keyword(s):  
Large Scale ◽  
K562 Cells ◽  
Cost Effective ◽  
Regulatory Elements ◽  
Nascent Transcript ◽  
Transcription Start Sites ◽  
The Road ◽  
Genome Wide ◽  
Active Enhancer ◽  
Effective Manner

Mounting evidence supports the idea that transcriptional patterns serve as more specific identifiers of active enhancers than histone marks; however, the optimal strategy to identify active enhancers both experimentally and computationally has not been determined. In this study, we compared 13 genome-wide RNA sequencing assays in K562 cells and showed that the nuclear run-on followed by cap-selection assay (namely, GRO/PRO-cap) has significant advantages in eRNA detection and active enhancer identification. We also introduced a new analytical tool, Peak Identifier for Nascent-Transcript Sequencing (PINTS), to identify active promoters and enhancers genome-wide and pinpoint the precise location of the 5′ transcription start sites (TSSs) within these regulatory elements. Finally, we compiled a comprehensive enhancer candidate compendium based on the detected eRNA TSSs available in 120 cell and tissue types. To facilitate the exploration and prioritization of these enhancer candidates, we also built a user-friendly web server (https://pints.yulab.org) for the compendium with various additional genomic and epigenomic annotations. With the knowledge of the best available assays and pipelines, this large-scale annotation of candidate enhancers will pave the road for selection and characterization of their functions in a time-, labor-, and cost-effective manner in future.

scholarly journals GWAS of DNA Methylation Variation Within Imprinting Control Regions Suggests Parent-of-Origin Association

2013 ◽  
Vol 16 (4) ◽  
pp. 767-781 ◽  
Author(s):  
Miguel E. Rentería ◽  
Marcel W. Coolen ◽  
Aaron L. Statham ◽  
R. Seong Min Choi ◽  
Wenjia Qu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Sample Size ◽  
Methylation Status ◽  
Regulatory Elements ◽  
Small Sample ◽  
Genetic Sequence ◽  
Suggestive Association ◽  
Genome Wide ◽  
Parent Of Origin ◽  
Control Regions

Imprinting control regions (ICRs) play a fundamental role in establishing and maintaining the non-random monoallelic expression of certain genes, via common regulatory elements such as non-coding RNAs and differentially methylated regions (DMRs) of DNA. We recently surveyed DNA methylation levels within four ICRs (H19-ICR, IGF2-DMR, KvDMR, and NESPAS-ICR) in whole-blood genomic DNA from 128 monozygotic (MZ) and 128 dizygotic (DZ) human twin pairs. Our analyses revealed high individual variation and intra-domain covariation in methylation levels across CpGs and emphasized the interaction between epigenetic variation and the underlying genetic sequence in a parent-of-origin fashion. Here, we extend our analysis to conduct two genome-wide screenings of single nucleotide polymorphisms (SNPs) underlying either intra-domain covariation or parent-of-origin-dependent association with methylation status at individual CpG sites located within ICRs. Although genome-wide significance was not surpassed due to sample size limitations, the most significantly associated SNPs found through multiple-trait genome-wide association (MQFAM) included the previously described rs10732516, which is located in the vicinity of the H19-ICR. Similarly, we identified an association between rs965808 and methylation status within the NESPAS-ICR. This SNP is positioned within an intronic region of the overlapping genes GNAS and GNAS-AS1, which are imprinted genes regulated by the NESPAS-ICR. Sixteen other SNPs located in regions apart from the analyzed regions displayed suggestive association with intra-domain methylation. Additionally, we identified 13 SNPs displaying parent-of-origin association with individual methylation sites through family-based association testing. In this exploratory study, we show the value and feasibility of using alternative GWAS approaches in the study of the interaction between epigenetic state and genetic sequence within imprinting regulatory domains. Despite the relatively small sample size, we identified a number of SNPs displaying suggestive association either in a domain-wide or in a parent-of-origin fashion. Nevertheless, these associations will require future experimental validation or replication in larger and independent samples.

scholarly journals DNABERT: pre-trained Bidirectional Encoder Representations from Transformers model for DNA-language in genome

2021 ◽  
Author(s):  
Yanrong Ji ◽  
Zhihan Zhou ◽  
Han Liu ◽  
Ramana V Davuluri
Keyword(s):  
Dna Sequences ◽  
Regulatory Elements ◽  
Ease Of Use ◽  
Fine Tuning ◽  
Supplementary Information ◽  
Sequence Motifs ◽  
Semantic Relationship ◽  
Accurate Identification ◽  
Conserved Sequence ◽  
Genome Wide

Abstract Motivation Deciphering the language of non-coding DNA is one of the fundamental problems in genome research. Gene regulatory code is highly complex due to the existence of polysemy and distant semantic relationship, which previous informatics methods often fail to capture especially in data-scarce scenarios. Results To address this challenge, we developed a novel pre-trained bidirectional encoder representation, named DNABERT, to capture global and transferrable understanding of genomic DNA sequences based on up and downstream nucleotide contexts. We compared DNABERT to the most widely used programs for genome-wide regulatory elements prediction and demonstrate its ease of use, accuracy and efficiency. We show that the single pre-trained transformers model can simultaneously achieve state-of-the-art performance on prediction of promoters, splice sites and transcription factor binding sites, after easy fine-tuning using small task-specific labeled data. Further, DNABERT enables direct visualization of nucleotide-level importance and semantic relationship within input sequences for better interpretability and accurate identification of conserved sequence motifs and functional genetic variant candidates. Finally, we demonstrate that pre-trained DNABERT with human genome can even be readily applied to other organisms with exceptional performance. We anticipate that the pre-trained DNABERT model can be fined tuned to many other sequence analyses tasks. Availability and implementation The source code, pretrained and finetuned model for DNABERT are available at GitHub (https://github.com/jerryji1993/DNABERT). Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals A genome-wide map of regulatory elements in zebrafish

Lab Animal ◽  
2020 ◽  
Vol 50 (1) ◽  
pp. 17-17
Author(s):  
Alexandra Le Bras
Keyword(s):  
Regulatory Elements ◽  
Genome Wide ◽  
A Genome

scholarly journals Epigenomic Analysis of RAD51 ChIP-seq Data Reveals cis-regulatory Elements Associated with Autophagy in Cancer Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2547
Author(s):  
Keunsoo Kang ◽  
Yoonjung Choi ◽  
Hyeonjin Moon ◽  
Chaelin You ◽  
Minjin Seo ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Homologous Recombination ◽  
Cell Lines ◽  
Regulatory Elements ◽  
Binding Motif ◽  
Genome Wide ◽  
E Box ◽  
Autophagy Pathway ◽  
Mcf 7

RAD51 is a recombinase that plays a pivotal role in homologous recombination. Although the role of RAD51 in homologous recombination has been extensively studied, it is unclear whether RAD51 can be involved in gene regulation as a co-factor. In this study, we found evidence that RAD51 may contribute to the regulation of genes involved in the autophagy pathway with E-box proteins such as USF1, USF2, and/or MITF in GM12878, HepG2, K562, and MCF-7 cell lines. The canonical USF binding motif (CACGTG) was significantly identified at RAD51-bound cis-regulatory elements in all four cell lines. In addition, genome-wide USF1, USF2, and/or MITF-binding regions significantly coincided with the RAD51-associated cis-regulatory elements in the same cell line. Interestingly, the promoters of genes associated with the autophagy pathway, such as ATG3 and ATG5, were significantly occupied by RAD51 and regulated by RAD51 in HepG2 and MCF-7 cell lines. Taken together, these results unveiled a novel role of RAD51 and provided evidence that RAD51-associated cis-regulatory elements could possibly be involved in regulating autophagy-related genes with E-box binding proteins.

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