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CTCF-RNA interactions orchestrate cell-specific chromatin loop organization [MicroC]

ABSTRACT: CCCTC-binding factor (CTCF) is essential for chromatin organization, but its role in dynamically shaping chromatin loops during cellular differentiation is not fully understood. We previously demonstrated that CTCF interacts with endogenous RNAs, and deletion of its ZF1 RNA-binding region disrupts chromatin loops in mouse embryonic stem cells (ESCs). Using an ESC-to-neural progenitor cell (NPC) differentiation model, we show that the ZF1 RNA-binding region of CTCF is crucial for maintaining cell-type specific chromatin loops. Expression of CTCF-∆ZF1 leads to dysregulation of genes within these disrupted loops, particularly those involved in neuronal development and function. We identified NPC-specific, CTCF-interacting RNAs and chose Podxl and Grb10 for further study. We found that CRISPR-Cas9-mediated truncation of Podxl and Grb10 disrupts chromatin loops in cis, similar to the disruption seen in the NPC-∆ZF1 mutant. Our study underscores the importance of CTCF-ZF1 RNA interactions in preserving cell-specific genome structure and cellular identity.

ORGANISM(S): Mus musculus

PROVIDER: GSE287376 | GEO | 2025/03/19

REPOSITORIES: GEO

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CTCF-RNA interactions orchestrate cell-specific chromatin loop organization [iCLIP2]

Project description:CCCTC-binding factor (CTCF) is essential for chromatin organization, but its role in dynamically shaping chromatin loops during cellular differentiation is not fully understood. We previously demonstrated that CTCF interacts with endogenous RNAs, and deletion of its ZF1 RNA-binding region disrupts chromatin loops in mouse embryonic stem cells (ESCs). Using an ESC-to-neural progenitor cell (NPC) differentiation model, we show that the ZF1 RNA-binding region of CTCF is crucial for maintaining cell-type specific chromatin loops. Expression of CTCF-∆ZF1 leads to dysregulation of genes within these disrupted loops, particularly those involved in neuronal development and function. We identified NPC-specific, CTCF-interacting RNAs and chose Podxl and Grb10 for further study. We found that CRISPR-Cas9-mediated truncation of Podxl and Grb10 disrupts chromatin loops in cis, similar to the disruption seen in the NPC-∆ZF1 mutant. Our study underscores the importance of CTCF-ZF1 RNA interactions in preserving cell-specific genome structure and cellular identity.

2025-03-19 | GSE287380 | GEO

CTCF-RNA interactions orchestrate cell-specific chromatin loop organization [RNA-seq]

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CTCF-RNA interactions orchestrate cell-specific chromatin loop organization [ChIP-seq]

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YY1 and CTCF Orchestrate a 3D Chromatin Looping Switch during Early Neural Lineage Commitment

Project description:CTCF is an architectural protein with a critical role in connecting higher-order chromatin folding in pluripotent stem cells. Recent reports have suggested that CTCF binding is more dynamic during development than previously appreciated. Here we set out to understand the extent to which shifts in genome-wide CTCF occupancy contribute to the 3-D reconfiguration of fine-scale chromatin folding during early neural lineage commitment. Unexpectedly, we observe a sharp decrease in CTCF occupancy during the transition from naïve/primed pluripotency to multipotent primary neural progenitor cells (NPCs). Many pluripotency gene-enhancer interactions are anchored by CTCF and its occupancy is lost in parallel with loop decommissioning during differentiation. Conversely, CTCF binding sites in NPCs are largely pre-existing in pluripotent stem cells. Only a small number of CTCF sites arise de novo in NPCs. We identify another zinc finger protein, Yin Yang 1 (YY1), at the base of looping interactions between NPC-specific genes and enhancers. Putative NPC-specific enhancers exhibit strong YY1 signal when engaged in 3-D contacts and negligible YY1 signal when not in loops. Moreover, siRNA knockdown of YY1 specifically disrupts interactions between key NPC enhancers and their target genes. YY1-mediated interactions between NPC regulatory elements are often nested within constitutive loops anchored by CTCF. Together, our results support a model in which YY1 acts as an architectural protein to connect developmentally regulated looping interactions; the location of YY1-mediated interactions may be demarcated in development by a pre-existing topological framework created by constitutive CTCF-mediated interactions.

2017-05-22 | GSE85185 | GEO

CTCF binding polarity determines chromatin looping [4C]

Project description:CCCTC-binding factor (CTCF) is an architectural protein involved in the three-dimensional organization of chromatin. In this study, we systematically assayed the 3D genomic contact profiles of hundreds of CTCF binding sites in multiple tissues with high-resolution 4C-seq. We find both developmentally stable and dynamic chromatin loops. As recently reported, our data also suggest that chromatin loops preferentially form between CTCF binding sites oriented in a convergent manner. To directly test this, we used CRISPR-Cas9 genome editing to delete core CTCF binding sites in three loci, including the CTCF site in the Sox2 super-enhancer. In all instances, CTCF and cohesin recruitment were lost, and chromatin loops with distal CTCF sites were disrupted or destabilized. Re-insertion of oppositely oriented CTCF recognition sequences restored CTCF and cohesin recruitment, but did not re-establish chromatin loops. We conclude that CTCF binding polarity plays a functional role in the formation of higher order chromatin structure. 4C-seq was performed on a large number of viewpoints in E14 embryonic stem cells, neural precursor cells and primary fetal liver cells

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Project description:Polycomb Repressive Complex 1 (PRC1) and CCCTC-binding factor (CTCF) are critical regulators of 3D chromatin architecture that influence cellular transcriptional programs. Spatial chromatin structures comprise of conserved compartments, topologically associating domains (TADs), and dynamic, cell-type-specific chromatin loops. Although the role of CTCF in chromatin organization is well-known, the involvement of PRC1 is less understood. In this study, we identified an unexpected, essential role for the canonical Pcgf2-containing PRC1 complex (cPRC1.2), a known transcriptional repressor, in activating bivalent genes during differentiation. Our Hi-C analysis revealed that cPRC1.2 forms chromatin loops at bivalent promoters, rendering them silent yet poised for activation. Using mouse embryonic stem cells (ESCs) with CRISPR/Cas9-mediated gene editing, we found that the loss of Pcgf2, though not affecting the global level of H2AK119ub1, disrupts these cPRC1.2 loops in ESCs and impairs the transcriptional induction of crucial target genes necessary for neuronal differentiation. Furthermore, we identified CTCF enrichment at cPRC1.2 loop anchors and at Polycomb group (PcG) bodies, nuclear foci with concentrated PRC1 and its tethered chromatin domains, suggesting that PRC1 and CTCF cooperatively shape chromatin loop structures. Through virtual 4C and other genomic analyses, we discovered that establishing neuronal progenitor cell (NPC) identity involves a switch from cPRC1.2-mediated chromatin loops to CTCF-mediated active loops, enabling the expression of critical lineage-specific factors. This study uncovers a novel mechanism by which pre-formed PRC1 and CTCF loops at lineage-specific genes maintain a poised state for subsequent gene activation, advancing our understanding of the role of chromatin architecture in controlling cell fate transitions.

2025-01-28 | GSE278946 | GEO

RNA interactions are essential for proper CTCF function

Project description:The function of the CCCTC-binding factor (CTCF) in the organization of the genome has become an important area of investigation, but the mechanisms by which CTCF dynamically contributes to genome organization are not clear. We previously discovered that CTCF binds to large numbers of endogenous RNAs, promoting its self-association. In this regard, we now report two independent features that disrupt CTCF association with chromatin: inhibition of transcription and disruption of CTCF-RNA interactions through mutations of two of its 11 zinc fingers which are not required for CTCF binding to its cognate DNA site: zinc finger-1 (ZF1) or -10 (ZF10). These mutations alter gene expression profiles as CTCF mutants lose their ability to form chromatin loops and thus, the ability to insulate chromatin domains as well as mediate CTCF long-range genomic interactions. Our results point to the importance of CTCF-mediated RNA interactions as a structural component of genome organization.

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Project description:Most cancer associated CTCF mutations are involved in the recognition of CTCF core binding motif. Interestingly, mutations of the currently uncharacterized ZF1 of CTCF are practically exclusive to breast cancer, where they are associated with increased metastatic ability and therapeutic resistance. Although unnecessary to bind the core-binding motif, it is still unknown if the ZF1 of CTCF promotes binding to an altered CTCF motif. Further, classical motif analysis tools are powerless to identify minute changes in core binding motif. Therefore, the biological and epigenetic mechanism of action of CTCF ZF1 mutations is still unexplored. In order to explain the impact of CTCF ZF1M in breast models, we developed a new tool, diffMotif, that allows the identification, at the single base-pair resolution, of extension or alteration of core binding motif. Using diffMotif, we identified an extension of CTCF core binding motif, necessitating a functional ZF1 to bind appropriately. Using a combination of ChIP-Seq and RNA-Seq, we discover that the inability to bind the extended motif led to altered gene expression driving increased invasive ability and drug metabolism, mimicking the harmful oncogenic phenotypes observed clinically. Our study demonstrates the oncologic relevance of the characterisation of mutation induced altered DNA binding ability, by diffMotif.

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Single base-pair resolution analysis of binding motif with diffMotif uncovers the oncogenic impact of CTCF mutations in breast cancer [ChIP-Seq]

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Cr(VI) Promotes Differential Binding of CTCF to its Cognate Sites

Project description:Using ChIP-seq, we characterize the differential binding of CTCF following 48 hours of low-dose, Cr(VI) treatment. Differentially-bound sites are enriched in regions near genes that are actively transcribed in the basal state and strength of initial binding may be a factor in determining the directionality of binding affinity fluctuations. CTCF and cohesin samples were used to predict intra-TAD chromatin loops in an effort to provide an initial characterization of how Cr(VI) potentially disrupts chromatin-chromatin contacts important for the regulation of transcription, serving as a foundation for future studies.

2020-07-21 | GSE154387 | GEO

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