Assessing the regulatory potential of transposable elements using chromatin accessibility profiles of maize transposons

Abstract Transposable elements (TEs) have the potential to create regulatory variation both through the disruption of existing DNA regulatory elements and through the creation of novel DNA regulatory elements. In a species with a large genome, such as maize, many TEs interspersed with genes create opportunities for significant allelic variation due to TE presence/absence polymorphisms among individuals. We used information on putative regulatory elements in combination with knowledge about TE polymorphisms in maize to identify TE insertions that interrupt existing accessible chromatin regions (ACRs) in B73 as well as examples of polymorphic TEs that contain ACRs among four inbred lines of maize including B73, Mo17, W22, and PH207. The TE insertions in three other assembled maize genomes (Mo17, W22, or PH207) that interrupt ACRs that are present in the B73 genome can trigger changes to the chromatin, suggesting the potential for both genetic and epigenetic influences of these insertions. Nearly 20% of the ACRs located over 2 kb from the nearest gene are located within an annotated TE. These are regions of unmethylated DNA that show evidence for functional importance similar to ACRs that are not present within TEs. Using a large panel of maize genotypes, we tested if there is an association between the presence of TE insertions that interrupt, or carry, an ACR and the expression of nearby genes. While most TE polymorphisms are not associated with expression for nearby genes, the TEs that carry ACRs exhibit enrichment for being associated with higher expression of nearby genes, suggesting that these TEs may contribute novel regulatory elements. These analyses highlight the potential for a subset of TEs to rewire transcriptional responses in eukaryotic genomes.

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Cis-regulatory elements within TEs can influence expression of nearby maize genes

10.1101/2020.05.20.107169 ◽

2020 ◽

Cited By ~ 3

Author(s):

Jaclyn M Noshay ◽

Alexandre P Marand ◽

Sarah N Anderson ◽

Peng Zhou ◽

Maria Katherine Mejia Guerra ◽

...

Keyword(s):

Allelic Variation ◽

Regulatory Elements ◽

Data Availability ◽

Transcriptional Responses ◽

Maize Genotypes ◽

Show Evidence ◽

The Many ◽

Dna Regulatory Elements ◽

Accessible Chromatin ◽

Eukaryotic Genomes

AbstractTransposable elements (TEs) have the potential to create regulatory variation both through disruption of existing DNA regulatory elements and through creation of novel DNA regulatory elements. In a species with a large genome, such as maize, the many TEs interspersed with genes creates opportunities for significant allelic variation due to TE presence/absence polymorphisms among individuals. We used information on putative regulatory elements in combination with knowledge about TE polymorphisms in maize to identify TE insertions that interrupt existing accessible chromatin regions (ACRs) in B73 as well as examples of polymorphic TEs that contain ACRs among four inbred lines of maize including B73, Mo17, W22, and PH207. The TE insertions in three other assembled maize genomes (Mo17, W22 or PH207) that interrupt ACRs that are present in the B73 genome can trigger changes to the chromatin suggesting the potential for both genetic and epigenetic influences of these insertions. Nearly 20% of the ACRs located over 2kb from the nearest gene are located within an annotated TE. These are regions of unmethylated DNA that show evidence for functional importance similar to ACRs that are not present within TEs. Using a large panel of maize genotypes we tested if there is an association between the presence of TE insertions that interrupt, or carry, an ACR and the expression of nearby genes. TEs that carry ACRs exhibit an enrichment for being associated with higher expression of nearby genes, suggesting that these TEs may create novel regulatory elements. These analyses highlight the potential for TEs to rewire transcriptional responses in eukaryotic genomes.Data AvailabilityIn this study we utilize previously published datasets that are available through the following accessions: SRX4727413, SRR8738272, and SRR8740852.

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Transposable elements as a potent source of diverse cis -regulatory sequences in mammalian genomes

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0347 ◽

2020 ◽

Vol 375 (1795) ◽

pp. 20190347 ◽

Cited By ~ 14

Author(s):

Vasavi Sundaram ◽

Joanna Wysocka

Keyword(s):

Gene Regulation ◽

Transposable Elements ◽

Regulatory Networks ◽

Regulatory Elements ◽

Regulatory Function ◽

Specific Gene ◽

Regulatory Sequences ◽

Dependent Manner ◽

Unique Contribution ◽

Regulatory Potential

Eukaryotic gene regulation is mediated by cis -regulatory elements, which are embedded within the vast non-coding genomic space and recognized by the transcription factors in a sequence- and context-dependent manner. A large proportion of eukaryotic genomes, including at least half of the human genome, are composed of transposable elements (TEs), which in their ancestral form carried their own cis -regulatory sequences able to exploit the host trans environment to promote TE transcription and facilitate transposition. Although not all present-day TE copies have retained this regulatory function, the preexisting regulatory potential of TEs can provide a rich source of cis -regulatory innovation for the host. Here, we review recent evidence documenting diverse contributions of TE sequences to gene regulation by functioning as enhancers, promoters, silencers and boundary elements. We discuss how TE-derived enhancer sequences can rapidly facilitate changes in existing gene regulatory networks and mediate species- and cell-type-specific regulatory innovations, and we postulate a unique contribution of TEs to species-specific gene expression divergence in pluripotency and early embryogenesis. With advances in genome-wide technologies and analyses, systematic investigation of TEs' cis -regulatory potential is now possible and our understanding of the biological impact of genomic TEs is increasing. This article is part of a discussion meeting issue ‘Crossroads between transposons and gene regulation’.

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The transcription factor GLI1 cooperates with the chromatin remodeler SMARCA2 to regulate chromatin accessibility at distal DNA regulatory elements

Journal of Biological Chemistry ◽

10.1074/jbc.ra120.013268 ◽

2020 ◽

Vol 295 (26) ◽

pp. 8725-8735

Author(s):

Stephanie L. Safgren ◽

Rachel L. O. Olson ◽

Anne M. Vrabel ◽

Luciana L. Almada ◽

David L. Marks ◽

...

Keyword(s):

Transcription Factor ◽

Transcriptional Activation ◽

Transcriptional Activity ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Micrococcal Nuclease ◽

Gene Promoters ◽

Interacting Protein ◽

Transcriptional Activation Domain ◽

Dna Regulatory Elements

The transcription factor GLI1 (GLI family zinc finger 1) plays a key role in the development and progression of multiple malignancies. To date, regulation of transcriptional activity at target gene promoters is the only molecular event known to underlie the oncogenic function of GLI1. Here, we provide evidence that GLI1 controls chromatin accessibility at distal regulatory regions by modulating the recruitment of SMARCA2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 2) to these elements. We demonstrate that SMARCA2 endogenously interacts with GLI1 and enhances its transcriptional activity. Mapping experiments indicated that the C-terminal transcriptional activation domain of GLI1 and SMARCA2's central domains, including its ATPase motif, are required for this interaction. Interestingly, similar to SMARCA2, GLI1 overexpression increased chromatin accessibility, as indicated by results of the micrococcal nuclease assay. Further, results of assays for transposase-accessible chromatin with sequencing (ATAC-seq) after GLI1 knockdown supported these findings, revealing that GLI1 regulates chromatin accessibility at several regions distal to gene promoters. Integrated RNA-seq and ATAC-seq data analyses identified a subset of differentially expressed genes located in cis to these regulated chromatin sites. Finally, using the GLI1-regulated gene HHIP (Hedgehog-interacting protein) as a model, we demonstrate that GLI1 and SMARCA2 co-occupy a distal chromatin peak and that SMARCA2 recruitment to this HHIP putative enhancer requires intact GLI1. These findings provide insights into how GLI1 controls gene expression in cancer cells and may inform approaches targeting this oncogenic transcription factor to manage malignancies.

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BET protein inhibition regulates macrophage chromatin accessibility and microbiota-dependent colitis

10.1101/2021.07.15.452570 ◽

2021 ◽

Author(s):

Michelle Hoffner O'Connor ◽

Ana Berglind ◽

Meaghan M Kennedy ◽

Benjamin P Keith ◽

Zachary J Lynch ◽

...

Keyword(s):

Gene Expression ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Inflammatory Gene Expression ◽

Chronic Inflammatory Response ◽

Inflammatory Gene ◽

Bet Inhibitor ◽

Dna Regulatory Elements ◽

Induced Changes

Introduction: In colitis, macrophage functionality is altered compared to homeostatic conditions. Loss of IL-10 signaling results in an inappropriate and chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice. Methods: We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence or absence of lipopolysaccharide (LPS) and with or without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization. Results: Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in the attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo reduced severity of colitis as compared with vehicle-treated mice. Conclusion: We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.

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Chromatin variation associated with liver metabolism is mediated by transposable elements

10.1101/052571 ◽

2016 ◽

Author(s):

Juan Du ◽

Amy Leung ◽

Candi Trac ◽

Brian W. Parks ◽

Aldons J. Lusis ◽

...

Keyword(s):

Transcription Factors ◽

Transposable Elements ◽

Complex Traits ◽

Phenotypic Diversity ◽

Enrichment Analysis ◽

Chromatin Accessibility ◽

Genomic Region ◽

Long Interspersed Nuclear Elements ◽

Accessible Chromatin ◽

High Sucrose

AbstractBackgroundFunctional regulatory regions in eukaryotic genomes are characterized by the disruption of nucleosomes leading to accessible chromatin. The modulation of chromatin accessibility is one of the key mediators of transcriptional regulation and variation in chromatin accessibility across individuals has been liked to complex traits and disease susceptibility. While mechanisms responsible for chromatin variation across individuals have been investigated, the overwhelming majority of chromatin variation remains unexplained. Furthermore, the processes through which the variation of chromatin accessibility contributes to phenotypic diversity remain poorly understood.ResultsWe profiled chromatin accessibility in liver from seven strains of mice with phenotypic diversity in response to a high-fat/high-sucrose (HF/HS) diet and identified reproducible chromatin variation across the genome. We found that sites of variable chromatin accessibility were more likely to coincide with particular classes of transposable elements (TEs) than sites with common chromatin features. Evolutionarily younger long interspersed nuclear elements (LINEs) are particularly enriched for variable chromatin sites. These younger LINEs are enriched for binding sites of immune-associated transcription factors, whereas older LINEs are enriched for liver-specific transcription factors. Genomic region enrichment analysis indicates that variable chromatin sites at TEs contribute to liver metabolic pathways. Finally, we show that polymorphism of TEs and differential DNA methylation at TEs can both contribute to chromatin variation.ConclusionsOur results demonstrate specific classes of TEs contribute to chromatin accessibility variation across strains of mice that display phenotypic diversity in response to a HF/HS diet. These results indicate that regulatory variation at TEs is an important contributor to phenotypic variation among populations.

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ATF3 drives senescence by reconstructing accessible chromatin profiles

10.1101/2020.08.13.249458 ◽

2020 ◽

Author(s):

Chao Zhang ◽

Xuebin Zhang ◽

Yiting Guan ◽

Xiaoke Huang ◽

Lijun Zhang ◽

...

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Transcription Factors ◽

Regulatory Mechanism ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Dynamic Landscape ◽

Intergenic Regions ◽

Senescence Program ◽

Accessible Chromatin

AbstractChromatin architecture and gene expression profile undergo tremendous reestablishment during senescence. However, the regulatory mechanism between chromatin reconstruction and gene expression in senescence remain elusive. The chromatin accessibility is an excellent perspective to reveal the latent regulatory elements. Thus, we depicted the landscapes of chromatin accessibility and gene expression during HUVECs senescence. We found that chromatin accessibilities are re-distributed during senescence. The senescence related increased accessible regions (IARs) and the decreased accessible regions (DARs) are mainly distributed in distal intergenic regions. The DARs are correlated with the function declines caused by senescence, whereas the IARs are involved in the regulation for senescence program. Moreover, the heterochromatin contributes most of IARs in senescent cells. We identified that the AP-1 transcription factors, especially ATF3 is responsible for driving chromatin accessibility reconstruction in IARs. In particular, DNA methylation is negatively correlated with chromatin accessibility during senescence. AP-1 motifs with low DNA methylation may improve their binding affinity in IARs and further opens the chromatin nearby. Our results described a dynamic landscape of chromatin accessibility whose remodeling contributes to the senescence program. And we identified a cellular senescence regulator, AP-1, which promotes senescence through organizing the accessibility profile in IARs.

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OPENANNO: annotating genomic regions with chromatin accessibility

10.1101/596627 ◽

2019 ◽

Cited By ~ 5

Author(s):

Shengquan Chen ◽

Yong Wang ◽

Rui Jiang

Keyword(s):

Cell Lines ◽

Regulatory Mechanism ◽

Association Studies ◽

Web Server ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Methodology Development ◽

Public Repositories ◽

Dna Regulatory Elements ◽

Genomic Regions

AbstractChromatin accessibility, as a powerful marker of active DNA regulatory elements, provides rich information to understand the regulatory mechanism. The revolution in high-throughput methods has accumulated massive chromatin accessibility profiles in public repositories as a valuable resource for machine learning and integrative studies. Nevertheless, utilization of these data is often hampered by the cumbersome and time-consuming collection, processing, and annotation of the chromatin accessibility information. Motivated by the above understanding, we developed a web server, named OPENANNO, to annotate the openness of genomic regions across diverse cell lines, tissues, and systems. The annotation is based on 871 DNase-seq experiments across 199 cell lines, 48 tissues, and 11 systems from ENCODE, and openness values rigorously defined by four statistical strategies. Particularly, we designed a parallel program to allow efficient annotation and visualization of the openness of a vast amount of genomic regions. OPENANNO will help users extract and download formulated data in a batch follow-up analysis. Besides, we illustrate the valuable information provided by OPENANNO using an enhancer of blood vessels from VISTA Enhancer Browser as an example. Furthermore, we demonstrate three applications of OPENANNO in regulatory mechanism and association studies. We believe that OPENANNO will serve as a comprehensive and user-friendly web server to facilitate methodology development and biological insights discovery, specifically to explore the biological questions and model the regulatory landscape of genome. OPENANNO is freely available at http://health.tsinghua.edu.cn/openness/anno/.

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ECOA-7. Conserved cell-lineage controlled chromatin accessibility in human and mouse glioblastoma stem cells predicts functionally distinct subgroups

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.007 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii2-ii2

Author(s):

Xi Lu ◽

Naga Prathyusha Maturi ◽

Malin Jarvius ◽

Linxuan Zhao ◽

Yuan Xie ◽

...

Keyword(s):

Stem Cells ◽

Epigenetic Regulation ◽

Regulatory Element ◽

Cell Lineage ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Cell Of Origin ◽

Glioblastoma Stem Cells ◽

Transcription Factor Motif ◽

Accessible Chromatin

Abstract There is ample support for developmental control of glioblastoma stem cells (GSCs), and a deeper knowledge of their epigenetic regulation could be central to more efficient glioblastoma (GBM) therapies. For this purpose, we analyzed the chromatin-accessibility landscape of nine mouse GSC cultures of defined cell of origin and 60 patient-derived GSC cultures by assay for transposase-accessible chromatin using sequencing (ATAC-seq). This uncovered an epigenetic variability of both mouse and human GSC cultures that differed from transcriptome clusters. Both mouse and human chromatin accessibility-guided clusters were predominantly determined by distal regulatory elements, displayed unique sets of transcription factor motif enrichment, and exhibited different functional and drug-response properties. Cross-species analysis of distal regulatory element regions in accessible chromatin of mouse and human cultures revealed conserved epigenetic regulation of GSCs.

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Stability of DNA methylation and chromatin accessibility in structurally diverse maize genomes

10.1101/2021.03.10.434810 ◽

2021 ◽

Author(s):

Jaclyn M Noshay ◽

Zhikai Liang ◽

Peng Zhou ◽

Peter A Crisp ◽

Alexandre P Marand ◽

...

Keyword(s):

Dna Methylation ◽

Sequence Variation ◽

Reference Genome ◽

De Novo ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Genome Context ◽

Genomic Regions ◽

Genome Assemblies ◽

Accessible Chromatin

AbstractAccessible chromatin and unmethylated DNA are associated with many genes and cis-regulatory elements. Attempts to understand natural variation for accessible chromatin regions (ACRs) and unmethylated regions (UMRs) often rely upon alignments to a single reference genome. This limits the ability to assess regions that are absent in the reference genome assembly and monitor how nearby structural variants influence variation in chromatin state. In this study, de novo genome assemblies for four maize inbreds (B73, Mo17, Oh43 and W22) are utilized to assess chromatin accessibility and DNA methylation patterns in a pan-genome context. The number of UMRs and ACRs that can be identified is more accurate when chromatin data is aligned to the matched genome rather than a single reference genome. While there are UMRs and ACRs present within genomic regions that are not shared between genotypes, these features are substantially enriched within shared regions, as determined by chromosomal alignments. Characterization of UMRs present within shared genomic regions reveals that most UMRs maintain the unmethylated state in other genotypes with only a small number being polymorphic between genotypes. However, the majority of UMRs between genotypes only exhibit partial overlaps suggesting that the boundaries between methylated and unmethylated DNA are dynamic. This instability is not solely due to sequence variation as these partially overlapping UMRs are frequently found within genomic regions that lack sequence variation. The ability to compare chromatin properties among individuals with structural variation enables pan-epigenome analyses to study the sources of variation for accessible chromatin and unmethylated DNA.Article summaryRegions of the genome that have accessible chromatin or unmethylated DNA are often associated with cis-regulatory elements. We assessed chromatin accessibility and DNA methylation in four structurally diverse maize genomes. There are accessible or unmethylated regions within the non-shared portions of the genomes but these features are depleted within these regions. Evaluating the dynamics of methylation and accessibility between genotypes reveals conservation of features, albeit with variable boundaries suggesting some instability of the precise edges of unmethylated regions.

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A combinatorial indexing strategy for epigenomic profiling of plant single cells

10.1101/2021.11.07.467612 ◽

2021 ◽

Author(s):

Xiaoyu Tu ◽

Alexandre P Marand ◽

Robert J. Schmitz ◽

Silin Zhong

Keyword(s):

Single Cell ◽

Single Cells ◽

Regulatory Elements ◽

Chromatin Accessibility ◽

Arabidopsis Root ◽

Indexing Method ◽

Specialized Equipment ◽

Cell Type Specific ◽

Accessible Chromatin ◽

Insight Into

Understanding how cis-regulatory elements facilitate gene expression is a key question in biology. Recent advances in single-cell genomics have led to the discovery of cell-specific chromatin landscapes that underlie transcription programs. However, the high equipment and reagent costs of commercial systems limit their applications for many laboratories. In this study, we profiled the Arabidopsis root single-cell epigenome using a combinatorial index and dual PCR barcode strategy without the need of any specialized equipment. We generated chromatin accessibility profiles for 13,576 Arabidopsis thaliana root nuclei with an average of 12,784 unique Tn5 integrations per cell and 85% of the Tn5 insertions localizing to discrete accessible chromatin regions. Comparison with data generated from a commercial microfluidic platform revealed that our method is capable of unbiased identification of cell type-specific chromatin accessibility with improved throughput, quality, and efficiency. We anticipate that by removing cost, instrument, and other technical obstacles, this combinatorial indexing method will be a valuable tool for routine investigation of single-cell epigenomes and usher new insight into plant growth, development and their interactions with the environment.

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