scholarly journals Transposable elements strongly contribute to cell-specific and species-specific looping diversity in mammalian genomes

2019 ◽  
Author(s):  
Adam G Diehl ◽  
Ningxin Ouyang ◽  
Alan P Boyle
Keyword(s):  
Transposable Elements ◽  
Large Fraction ◽  
Population Level ◽  
Cell Types ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
3D Genome ◽  
Chromatin Looping ◽  
Mammalian Genomes ◽  
Species Specific

AbstractBackgroundChromatin looping is exceedingly important to gene regulation and a host of other nuclear processes. Many recent insights into 3D chromatin structure across species and cell types have contributed to our understanding of the principles governing chromatin looping. However, 3D genome evolution and how it relates to Mendelian selection remain largely unexplored. CTCF, an insulator protein found at most loop anchors, has been described as the “master weaver” of mammalian genomes, and variations in CTCF occupancy are known to influence looping divergence. A large fraction of mammalian CTCF binding sites fall within transposable elements (TEs) but their contributions to looping variation are unknown. Here we investigated the effect of TE-driven CTCF binding site expansions on chromatin looping in human and mouse.ResultsTEs have broadly contributed to CTCF binding and loop boundary specification, primarily forming variable loops across species and cell types and contributing nearly 1/3 of species-specific and cell-specific loops.ConclusionsOur results demonstrate that TE activity is a major source of looping variability across species and cell types. Thus, TE-mediated CTCF expansions explain a large fraction of population-level looping variation and may play a role in adaptive evolution.

scholarly journals Co-opted transposons help perpetuate conserved higher-order chromosomal structures

2018 ◽  
Author(s):  
Mayank NK Choudhary ◽  
Ryan Z Friedman ◽  
Julia T Wang ◽  
Hyo Sik Jang ◽  
Xiaoyu Zhuo ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Binding Site ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Genome Architecture ◽  
3D Genome ◽  
Domain Structures ◽  
Architectural Proteins ◽  
Mammalian Genomes ◽  
Species Specific

ABSTRACTTransposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include architectural proteins—such as CTCF, RAD21 and SMC3—that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed. Here we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice via deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species via CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to a collapse of such conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time. TEs have long been considered a source of genetic innovation; by examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.One-sentence summaryCo-option of transposable elements maintains conserved 3D genome structures via CTCF binding site turnover in human and mouse.

scholarly journals Co-opted transposons help perpetuate conserved higher-order chromosomal structures

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Mayank NK Choudhary ◽  
Ryan Z. Friedman ◽  
Julia T. Wang ◽  
Hyo Sik Jang ◽  
Xiaoyu Zhuo ◽  
...  
Keyword(s):  
Binding Sites ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Genome Architecture ◽  
Mutational Signatures ◽  
Domain Structures ◽  
Domain Boundaries ◽  
Architectural Proteins ◽  
Mammalian Genomes ◽  
Species Specific

Abstract Background Transposable elements (TEs) make up half of mammalian genomes and shape genome regulation by harboring binding sites for regulatory factors. These include binding sites for architectural proteins, such as CTCF, RAD21, and SMC3, that are involved in tethering chromatin loops and marking domain boundaries. The 3D organization of the mammalian genome is intimately linked to its function and is remarkably conserved. However, the mechanisms by which these structural intricacies emerge and evolve have not been thoroughly probed. Results Here, we show that TEs contribute extensively to both the formation of species-specific loops in humans and mice through deposition of novel anchoring motifs, as well as to the maintenance of conserved loops across both species through CTCF binding site turnover. The latter function demonstrates the ability of TEs to contribute to genome plasticity and reinforce conserved genome architecture as redundant loop anchors. Deleting such candidate TEs in human cells leads to the collapse of conserved loop and domain structures. These TEs are also marked by reduced DNA methylation and bear mutational signatures of hypomethylation through evolutionary time. Conclusions TEs have long been considered a source of genetic innovation. By examining their contribution to genome topology, we show that TEs can contribute to regulatory plasticity by inducing redundancy and potentiating genetic drift locally while conserving genome architecture globally, revealing a paradigm for defining regulatory conservation in the noncoding genome beyond classic sequence-level conservation.

scholarly journals Tandem Directional CTCF Sites Balance Protocadherin Promoter Usage

2019 ◽  
Author(s):  
Qiang Wu ◽  
Ya Guo ◽  
Yujia Lu ◽  
Jingwei Li ◽  
Yonghu Wu ◽  
...  
Keyword(s):  
Single Cells ◽  
Computational Simulation ◽  
Ctcf Binding ◽  
Monoallelic Expression ◽  
3D Genome ◽  
Genome Wide ◽  
A Genome ◽  
Mammalian Genomes ◽  
Wide Scale ◽  
Promoter Usage

ABSTRACTCTCF is a key insulator-binding protein and mammalian genomes contain numerous CTCF-binding sites (CBSs), many of which are organized in tandem arrays. Here we provide direct evidence that CBSs, if located between enhancers and promoters in the Pcdhα and β-globin clusters, function as an enhancer-blocking insulator by forming distinct directional chromatin loops, regardless whether enhancers contain CBS or not. Moreover, computational simulation and experimental capture revealed balanced promoter usage in cell populations and stochastic monoallelic expression in single cells by large arrays of tandem variable CBSs. Finally, gene expression levels are negatively correlated with CBS insulators located between enhancers and promoters on a genome-wide scale. Thus, single CBS insulators ensure proper enhancer insulation and promoter activation while tandem-arrayed CBS insulators determine balanced promoter usage. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.

scholarly journals Determining cellular CTCF and cohesin abundances to constrain 3D genome models

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Claudia Cattoglio ◽  
Iryna Pustova ◽  
Nike Walther ◽  
Jaclyn J Ho ◽  
Merle Hantsche-Grininger ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Site Occupancy ◽  
Cellular Protein ◽  
Protein Quantification ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
3D Genome ◽  
Quantitative Measurements ◽  
Dna Loop ◽  
Predictive Understanding

Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here, we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.

scholarly journals Determining cellular CTCF and cohesin abundances to constrain 3D genome models

2018 ◽  
Author(s):  
Claudia Cattoglio ◽  
Iryna Pustova ◽  
Nike Walther ◽  
Jaclyn J. Ho ◽  
Merle Hantsche-Grininger ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Site Occupancy ◽  
Cellular Protein ◽  
Protein Quantification ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
3D Genome ◽  
Quantitative Measurements ◽  
Dna Loop ◽  
Predictive Understanding

Achieving a quantitative and predictive understanding of 3D genome architecture remains a major challenge, as it requires quantitative measurements of the key proteins involved. Here we report the quantification of CTCF and cohesin, two causal regulators of topologically associating domains (TADs) in mammalian cells. Extending our previous imaging studies (Hansen et al., 2017), we estimate bounds on the density of putatively DNA loop-extruding cohesin complexes and CTCF binding site occupancy. Furthermore, co-immunoprecipitation studies of an endogenously tagged subunit (Rad21) suggest the presence of cohesin dimers and/or oligomers. Finally, based on our cell lines with accurately measured protein abundances, we report a method to conveniently determine the number of molecules of any Halo-tagged protein in the cell. We anticipate that our results and the established tool for measuring cellular protein abundances will advance a more quantitative understanding of 3D genome organization, and facilitate protein quantification, key to comprehend diverse biological processes.

scholarly journals Functional signatures of evolutionarily young CTCF binding sites

2020 ◽  
Author(s):  
Dhoyazan Azazi ◽  
Jonathan M. Mudge ◽  
Duncan T. Odom ◽  
Paul Flicek
Keyword(s):  
Mus Musculus ◽  
Binding Sites ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Mus Musculus Domesticus ◽  
Transcription Start Sites ◽  
Regulatory Architecture ◽  
Topologically Associated Domains ◽  
Species Specific ◽  
The Impact

ABSTRACTThe introduction of novel CTCF binding sites in gene regulatory regions in the rodent lineage is partly the effect of transposable element expansion. The exact mechanism and functional impact of evolutionarily novel CTCF binding sites are not yet fully understood. We investigated the impact of novel species-specific CTCF binding sites in two Mus genus subspecies, Mus musculus domesticus and Mus musculus castaneus, that diverged 0.5 million years ago. The activity of the B2-B4 family of transposable elements independently in both lineages leads to the proliferation of novel CTCF binding sites. A subset of evolutionarily young sites may harbour transcriptional functionality, as evidenced by the stability of their binding across multiple tissues in M. musculus domesticus (BL6), while overall the distance of species-specific CTCF binding to the nearest transcription start sites and/or topologically-associated domains (TADs) is largely similar to musculus-common CTCF sites. Remarkably, we discovered a recurrent regulatory architecture consisting of a CTCF binding site and an interferon gene that appears to have been tandemly duplicated to create a 15-gene cluster on chromosome 4, thus forming a novel BL6 specific immune locus, in which CTCF may play a regulatory role. Our results demonstrate that thousands of CTCF binding sites show multiple functional signatures rapidly after incorporation into the genome.

scholarly journals Comprehensive genomic analysis reveals dynamic evolution of endogenous retroviruses that code for retroviral-like protein domains

2019 ◽  
Author(s):  
Mahoko Takahashi Ueda ◽  
Kirill Kryukov ◽  
Satomi Mitsuhashi ◽  
Hiroaki Mitsuhashi ◽  
Tadashi Imanishi ◽  
...  
Keyword(s):  
Host Species ◽  
Transcription Initiation ◽  
Protein Domains ◽  
Genomic Analysis ◽  
Cell Types ◽  
Endogenous Retroviruses ◽  
Open Reading Frames ◽  
Specific Expression ◽  
Mammalian Genomes ◽  
Species Specific

AbstractEndogenous retroviruses (ERVs) are remnants of ancient retroviral infections of mammalian germline cells. A large proportion of ERVs lose their open reading frames (ORFs), while others retain them and become exapted by the host species. However, it remains unclear what proportion of ERVs possess ORFs (ERV-ORFs), become transcribed, and serve as candidates for co-opted genes. Hence, we investigated characteristics of 176,401 ERV-ORFs containing retroviral-like protein domains (gag, pro, pol, and env) in 19 mammalian genomes. The fractions of ERVs possessing ORFs were overall small (∼0.15%) although they varied depending on domain types as well as species. The observed divergence of ERV-ORF from their consensus sequences suggested that a large proportion of ERV-ORFs either recently or anciently inserted themselves into mammalian genomes. Alternatively, very few ERVs lacking ORFs were found to exhibit similar divergence patterns. To identify ERV-ORFs transcribed as proteins, we compared ERV-ORFs with various multi-omics data including transcriptome data, trimethylation at histone H3 lysine 36, and transcription initiation sites from 2,834 cell types, and found 408 and 752 ERV-ORFs, accounting for 2-3% of all ERV-ORFs, with high transcriptional potential in humans and mice, respectively. Moreover, many of these ERV-ORFs with transcriptional potential were lineage-specific sequences exhibiting tissue-specific expression. These results suggest a possibility for the expression of uncharacterized functional genes containing ERV-ORFs hidden within mammalian genomes. Together, our analyses suggest that more ERV-ORFs may be co-opted in a host-species specific manner than we currently know, which are likely to have contributed to mammalian evolution and diversification.

scholarly journals NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Priscillia Lhoumaud ◽  
Sana Badri ◽  
Javier Rodriguez-Hernaez ◽  
Theodore Sakellaropoulos ◽  
Gunjan Sethia ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Chromatin Modifications ◽  
3D Genome ◽  
Topologically Associating Domain ◽  
Bidirectional Relationship ◽  
Oncogene Activation ◽  
Transcriptional Changes ◽  
Low Levels

Abstract CTCF and cohesin play a key role in organizing chromatin into topologically associating domain (TAD) structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma, a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2, resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, here we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A logistic regression model reveals that differentially expressed genes are significantly enriched within the same insulated domain as altered H3K27ac and CTCF peaks. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.

scholarly journals NSD2 overexpression drives clustered chromatin and transcriptional changes in a subset of insulated domains

2019 ◽  
Author(s):  
Priscillia Lhoumaud ◽  
Sana Badri ◽  
Javier Rodriguez Hernaez ◽  
Theodore Sakellaropoulos ◽  
Gunjan Sethia ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Ctcf Binding ◽  
Ctcf Binding Site ◽  
Chromatin Modifications ◽  
3D Genome ◽  
Bidirectional Relationship ◽  
Oncogene Activation ◽  
Transcriptional Changes ◽  
Low Levels ◽  
Gene Sharing

AbstractCTCF and cohesin play a key role in organizing chromatin into TAD structures. Disruption of a single CTCF binding site is sufficient to change chromosomal interactions leading to alterations in chromatin modifications and gene regulation. However, the extent to which alterations in chromatin modifications can disrupt 3D chromosome organization leading to transcriptional changes is unknown. In multiple myeloma a 4;14 translocation induces overexpression of the histone methyltransferase, NSD2 resulting in expansion of H3K36me2 and shrinkage of antagonistic H3K27me3 domains. Using isogenic cell lines producing high and low levels of NSD2, we find oncogene activation is linked to alterations in H3K27ac and CTCF within H3K36me2 enriched chromatin. A linear regression model reveals that changes in both CTCF and/or H3K27ac significantly increase the probability that a gene sharing the same insulated domain will be differentially expressed. These results identify a bidirectional relationship between 2D chromatin and 3D genome organization in gene regulation.

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