CTCF-Mediated Functional Chromatin Interactome in Pluripotent Cells

By Lusy Handoko, Han Xu, Guoliang Li, C. Ngan, E. Chew, Marie Schnapp, C. Lee, Chaopeng Ye, Joanne Lim Hui Ping, F. Mulawadi and 12 more. Nature Genetics, 2011

662 citations recorded by the source corpus.

Mammalian genomes are viewed as functional organizations that orchestrate spatial and temporal gene regulation. CTCF, the most characterized insulator-binding protein, has been implicated as a key genome organizer. However, little is known about CTCF-associated higher-order chromatin structures at a global scale. Here we applied chromatin interaction analysis by paired-end tag (ChIA-PET) sequencing to elucidate the CTCF-chromatin interactome in pluripotent cells. From this analysis, we identified 1,480 cis- and 336 trans-interacting loci with high reproducibility and precision. Associating these chromatin interaction loci with their underlying epigenetic states, promoter activities, enhancer binding and nuclear lamina occupancy, we uncovered five distinct chromatin domains that suggest potential new models of CTCF function in chromatin organization and transcriptional control. Specifically, CTCF interactions demarcate chromatin-nuclear membrane attachments and influence proper gene expression through extensive cross-talk between promoters and regulatory elements. This highly complex nuclear organization offers insights toward the unifying principles that govern genome plasticity and function.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/6464faf6a2a656bb6d8dc887864694ef2e934608

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

1. W. de Laat
2. Bing Ren
3. E. de Wit
4. Leonid A. Mirny
5. Amos Tanay
6. V. Corces
7. Michael Snyder
8. Erik Splinter

In Molecular Biology

1. Richard A. Young
2. W. de Laat
3. Denes Hnisz
4. Tong Ihn Lee
5. Bing Ren
6. Job Dekker
7. Leonid A. Mirny
8. E. de Wit

Citations in the corpus

• Exploring the three-dimensional organization of genomes: interpreting chromatin interaction data (2013, background): “The role of this class of looping interactions in gene regulation is not fully understood, but a general architectural role seems likely 31,51,52 .”
• CTCF Binding Polarity Determines Chromatin Looping. (2015, background): “There aremanymoreCTCFbinding sites thanTADboundaries, and CTCF sites also far outnumber chromatin loops currently found per cell type (Handoko et al., 2011; Rao et al., 2014).”
• Genome-wide analyses of chromatin interactions after the loss of Pol I, Pol II, and Pol III (2020, neutral): “4e), constrained within CTCF loop domains [58, 59].”
• A decade of 3C technologies: insights into nuclear organization. (2012, methodology): “In mammals, CTCF sites form chromatin loops by contacting each other in the b-globin locus (Splinter et al. 2006) and H19/Igf2 locus (Zhao et al. 2006).”
• Three-dimensional folding and functional organization principles of the Drosophila genome. (2012, methodology): “…sequencing to globally map chromatin contacts in human (Lieberman-Aiden et al., 2009; the Hi-C method) and yeast (Duan et al., 2010; Tanizawa et al., 2010), or of subsets of genomic interactions between regions bound by regulatory factors (Fullwood et al., 2009; Handoko et al., 2011).”
• Control of cell identity genes occurs in insulated neighborhoods in mammalian chromosomes (2014, positive): “CTCF has previously been shown to be associated with boundary formation, insulator activity and transcriptional regulation (Bell et al., 1999; Denholtz et al., 2013; Felsenfeld et al., 2004; Handoko et al., 2011; Kim et al., 2007; Phillips and Corces, 2009; Schwartz et al., 2012; Sexton et al., 2012”
• Extensive Promoter-centered Chromatin Interactions Provide a Topological Basis for Transcription Regulation (2012, positive): “The interacting regions can be established and/or maintained by potential chromatin bridging proteins such as cohesins (Merkenschlager, 2010) and CTCF (Handoko et al., 2011), and this process might be facilitated by chromatin remodeling proteins (Euskirchen et al.”
• CRISPR Inversion of CTCF Sites Alters Genome Topology and Enhancer/Promoter Function (2015, positive): “…genome-wide CBS orientation and CTCF/cohesin-mediated DNA-looping topology by analyzing published datasets of chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and ChIP-seq with specific CTCF/cohesin antibodies (ENCODE Project Consortium, 2012; Handoko et al., 2011).”
• Architectural protein subclasses shape 3D organization of genomes during lineage commitment. (2013, positive): “Mediator and Cohesin Bridge Proximal EnhancerPromoter Interactions To understand the organizing principles regulating celltype-specific chromatin architecture, we first examined CTCF-independent Smc1 sites that were occupied only in ES cells and then lost upon differentiation (n = 123) (Figures 5B a”
• Activation of proto-oncogenes by disruption of chromosome neighborhoods (2015, background): “Previous studies have established that CTCF is bound at the anchor sites of chromosome loop structures, but not every CTCF-bound site in the genome is involved in looping interactions, and the CTCF-bound sites that are detected at the boundaries at looping interactions tend to be co-bound by cohesin”
• Regulation of disease-associated gene expression in the 3D genome (2016, positive): “CTCF can form chroma­ tin loops between dispersed binding sites 82,83 , possibly through self­dimerization 84 or via the recruitment of cohesin 85–88 , a ring­shaped protein complex that can embrace two double­stranded DNA helices (reviewed in REF.”