CTCF: an architectural protein bridging genome topology and function

Ong, Chin‐Tong; Corcés, Victor G.

doi:10.1038/nrg3663

Cited by 924 publications

(918 citation statements)

References 101 publications

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“…The DNA binding protein CCCTCbinding factor (CTCF) is instrumental for the 3D organization of the chromatin. CTCF, which is highly enriched at TAD borders (21), facilitates the formation of DNA loops that form between CTCF binding sites because of their attracting and interacting converging (head-to-head) orientations (10). Consistently, CTCF ChIP-seq data from human and mouse cells revealed several mammalian conserved CTCF sites at the deeply conserved Six TAD borders (Fig.…”

Section: Resultssupporting

confidence: 54%

Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders

Gómez-Marín

Tena

Acemel

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

152

147

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Increasing evidence in the last years indicates that the vast amount of regulatory information contained in mammalian genomes is organized in precise 3D chromatin structures. However, the impact of this spatial chromatin organization on gene expression and its degree of evolutionary conservation is still poorly understood. The Six homeobox genes are essential developmental regulators organized in gene clusters conserved during evolution. Here, we reveal that the Six clusters share a deeply evolutionarily conserved 3D chromatin organization that predates the Cambrian explosion. This chromatin architecture generates two largely independent regulatory landscapes (RLs) contained in two adjacent topological associating domains (TADs). By disrupting the conserved TAD border in one of the zebrafish Six clusters, we demonstrate that this border is critical for preventing competition between promoters and enhancers located in separated RLs, thereby generating different expression patterns in genes located in close genomic proximity. Moreover, evolutionary comparison of Six-associated TAD borders reveals the presence of CCCTC-binding factor (CTCF) sites with diverging orientations in all studied deuterostomes. Genomewide examination of mammalian HiC data reveals that this conserved CTCF configuration is a general signature of TAD borders, underscoring that common organizational principles underlie TAD compartmentalization in deuterostome evolution.CTCF | TAD | Six cluster | regulatory landscapes | evolution

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Section: Resultssupporting

confidence: 54%

Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders

Gómez-Marín

Tena

Acemel

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

152

147

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“…Although loss of CTCF was shown to result in spreading of H3K27me3 at the HoxA locus (45), no evidence of H3K27me3 spreading was detected following CTCF knockdown in Drosophila (43,46,47). Therefore, the domain barrier activity of CTCF has remained inconclusive (43,48). Our results showing disruption of H3K9me2 domain boundaries at weak CTCF-binding sites suggest a role for CTCF in H3K9me2 domain maintenance.…”

Section: Discussionmentioning

confidence: 52%

“…Previously, several studies, including ours, have suggested a role for CTCF in establishing functional expression domains (3,43,44). Although loss of CTCF was shown to result in spreading of H3K27me3 at the HoxA locus (45), no evidence of H3K27me3 spreading was detected following CTCF knockdown in Drosophila (43,46,47). Therefore, the domain barrier activity of CTCF has remained inconclusive (43,48).…”

Section: Discussionmentioning

confidence: 74%

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Jose

Jagannathan

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Investigations into the genomic landscape of histone modifications in heterochromatic regions have revealed histone H3 lysine 9 dimethylation (H3K9me2) to be important for differentiation and maintaining cell identity. H3K9me2 is associated with gene silencing and is organized into large repressive domains that exist in close proximity to active genes, indicating the importance of maintenance of proper domain structure. Here we show that nickel, a nonmutagenic environmental carcinogen, disrupted H3K9me2 domains, resulting in the spreading of H3K9me2 into active regions, which was associated with gene silencing. We found weak CCCTC-binding factor (CTCF)-binding sites and reduced CTCF binding at the Ni-disrupted H3K9me2 domain boundaries, suggesting a loss of CTCF-mediated insulation function as a potential reason for domain disruption and spreading. We furthermore show that euchromatin islands, local regions of active chromatin within large H3K9me2 domains, can protect genes from H3K9me2-spreadingassociated gene silencing. These results have major implications in understanding H3K9me2 dynamics and the consequences of chromatin domain disruption during pathogenesis.insulator | nickel toxicity | nickel carcinogenesis

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“…DNA methylation has been reported to regulate CTCF binding to DNA, which in turn regulates gene expression through long range interactions with enhancers and promoters [25]. Thus, we suggest that this methylation of CTCF is important in the aging process.…”

Section: Discussionmentioning

confidence: 59%

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

et al. 2018

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Age-related changes in DNA methylation were observed in cross-sectional studies, but longitudinal evidence is still limited. Here, we aimed to characterize longitudinal age-related methylation patterns using 1011 blood samples collected from 385 Swedish twins (age at entry: mean 69 and standard deviation 9.7, 73 monozygotic and 96 dizygotic pairs) up to five times (mean 2.6) over 20 years (mean 8.7). We identified 1316 age-associated methylation sites (P<1.3×10−7) using a longitudinal epigenome-wide association study design. We measured how estimated cellular compositions changed with age and how much they confounded the age effect. We validated the results in two independent longitudinal cohorts, where 118 CpGs were replicated in Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS, 390 samples) (P<3.9×10−5), 594 in Lothian Birth Cohort (LBC, 3018 samples) (P<5.1×10−5) and 63 in both. Functional annotation of age-associated CpGs showed enrichment in CCCTC-binding factor (CTCF) and other transcription factor binding sites. We further investigated genetic influences on methylation and found no interaction between age and genetic effects in the 1316 age-associated CpGs. Moreover, in the same CpGs, methylation differences within twin pairs increased with 6.4% over 10 years, where monozygotic twins had smaller intra-pair differences than dizygotic twins. In conclusion, we show that age-related methylation changes persist in a longitudinal perspective, and are fairly stable across cohorts. The changes are under genetic influence, although this effect is independent of age. Moreover, methylation variability increase over time, especially in age-associated CpGs, indicating the increase of environmental contributions on DNA methylation with age.

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CTCF: an architectural protein bridging genome topology and function

Cited by 924 publications

References 101 publications

Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders

Evolutionary comparison reveals that diverging CTCF sites are signatures of ancestral topological associating domains borders

Epigenetic dysregulation by nickel through repressive chromatin domain disruption

Epigenetic influences on aging: a longitudinal genome-wide methylation study in old Swedish twins

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