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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [III]

ABSTRACT: CTCF 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 clustered Pcdh and b-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 vivo 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 choice. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.

ORGANISM(S): Mus musculus

PROVIDER: GSE138645 | GEO | 2020/03/01

REPOSITORIES: GEO

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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [V]

Project description:CTCF 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 clustered Pcdh and b-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 vivo 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 choice. This finding has interesting implications on the role of topological insulators in 3D genome folding and developmental gene regulation.

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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [II]

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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [I]

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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [IV]

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Tandem CTCF sites function as insulators to balance spatial chromatin contacts and topological enhancer-promoter selection [VI]

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Project description:The architectural protein CTCF binds to mammalian insulators genome wide with directionality and recruits cohesin to mediate oriented long-distance chromatin loops. In many cases, CTCF-binding sites (CBSs) are associated with distal enhancers and target promoters. It is generally thought that CTCF binding results in spatial contacts between distal enhancers and target promoters leading to activation of specific promoters. However, how CTCF orchestrates higher-order chromatin organization to regulate gene expression is not fully understood. Here we used CRISPR DNA-fragment editing to investigate the roles of CTCF in chromatin organization of the clustered protocadherin (Pcdh) genes, which is an ideal model system with repertoires of CBSs in variable promoters and super-enhancers. We found that the CBSs at chromatin domain boundary and even single CBSs could determine the orientation of long-distance chromatin looping. In addition, deletion or inversion of large regions containing tandem CBS arrays in mice demonstrated asymmetric influences on chromatin looping between super-enhancers and target promoters. These genetic data have important implications on the assembly mechanisms of higher-order chromatin structures.

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Low affinity CTCF binding drives transcriptional regulation whereas high affinity binding encompasses architectural functions.

Project description:This SuperSeries is composed of the SubSeries listed below. CTCF is a DNA-binding protein which plays critical roles in chromatin structure organization and transcriptional regulation; however, little is known about the functional determinants of different CTCF binding sites (CBS). Using a conditional mouse model, we have identified one set of CBSs that are lost upon CTCF depletion (lost CBSs) and another set that persists (retained CBSs). Retained CBSs are more similar to the consensus CTCF binding sequence and usually span tandem CTCF peaks. Lost CBSs are enriched at enhancers and promoters and associate with active chromatin marks and higher transcriptional activity. In contrast, retained CBSs are enriched at TAD and loop boundaries. Integration of ChIP-seq and RNA-seq data has revealed that retained CBSs are located at the boundaries between distinct chromatin states, acting as chromatin barriers. Our results provide evidence that transient, lost CBSs are involved in transcriptional regulation, whereas retained CBSs are critical for establishing higher-order chromatin architecture.

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Project description:CTCF/cohesin play a central role in insulator function and higher-order chromatin organization of mammalian genomes. Recent studies identified a correlation between the orientation of CTCF-binding sites (CBSs) and chromatin loops. To test the functional significance of this observation, we combined CRISPR/Cas9-based genomic-DNA-fragment editing with chromosome-conformation-capture experiments to show that the location and relative orientations of CBSs determine the specificity of long-range chromatin looping in mammalian genomes, using protocadherin (Pcdh) and β-globin as model genes. Inversion of CBS elements within the Pcdh enhancer reconfigures the topology of chromatin loops between the distal enhancer and target promoters, and alters gene-expression patterns. Thus, although enhancers can function in an orientation-independent manner in reporter assays, in the native chromosome context the orientation of at least some enhancers carrying CBSs can determine both the architecture of topological chromatin domains and enhancer/promoter specificity. The findings reveal how 3D chromosome architecture can be encoded by genome sequence.

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