CTCF as a regulator of alternative splicing: new tricks for an old player

Alharbi, Adel B.; Schmitz, Ulf; Bailey, Charles G.; Rasko, John E.J.

doi:10.1093/nar/gkab520

Cited by 39 publications

(42 citation statements)

References 143 publications

(280 reference statements)

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“…However, in this case, it remains unclear how CTCF could specifically promotes the expression of circESRP1 but not linear RNA. It is speculated that this may be because ESRP1 is also an important splicing factor [ 20 , 36 , 37 ] or circRNA has higher stability [ 8 , 35 ]. Recent years, convincing evidences has also linked CTCF to modulation of alternative splicing (AS) at both the transcriptome-wide level and individual transcript [ 38 , 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…CircESRP1 overexpression impaired the stimulating effects of CTCF knockdown on c-Myc and EMT. Previous studies proved that CTCF could interact with c-Myc promoter elements and represses its transcription [ 30 , 37 ], thus the constructing of circESRP1/miR-3942-5p/CTCF feedback loop could finally inhibit RCC EMT progression via restricting the expression of c-Myc. Previous studies indicated that CTCF was a master regulator of gene expression, and the functions of which were complicated.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies indicated that CTCF was a master regulator of gene expression, and the functions of which were complicated. It can function as a transcriptional activator and repressor, as well as a chromatin insulator etc [ 37 ]. Both Yang et al [ 42 ] and Vostrov et al [ 43 ] demonstrated that CTCF can bind the promoter of the amyloid b-protein precursor (APP) gene and promoted its transcriptional activation.…”

Section: Discussionmentioning

confidence: 99%

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CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop

et al. 2021

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Circular RNA (circRNA), a closed continuous loop formed by back-splicing, has been confirmed to be implicated in a variety of human diseases including cancers. However, the underlying molecular mechanism of circRNA regulating the progression of renal cell carcinoma (RCC) remains largely unclear. In the present study, we identified a novel circular RNA, circESRP1, that derived from the ESRP1 gene locus at 8q22.1 exons. Lower expression of circESRP1 was found in clear cell RCC (ccRCC) tissues and cell lines. Besides, circESRP1 expression level showed inversely correlated with the advanced tumor size, TNM stage and distant metastasis of ccRCC. The expression level of circESRP1 exhibited a positive correlation with CTCF protein but negatively correlated with miR-3942 in 79 ccRCC tissues. In vivo experiments, we found that overexpression of circESRP1 effectively repressed xenograft tumor growth and inhibited c-Myc-mediated EMT progression. CircESRP1 acted as a sponge to competitively bind with miR-3942 as confirmed through RNA pull-down, RIP and dual-luciferase reporter assays. Moreover, CTCF, a downstream target of miR-3942, was validated to specifically promote the circESRP1 transcript expression and regulated by circESRP1/miR-3942 pathway to form a positive feedback loop. We also revealed that the circESRP1/miR-3942/CTCF feedback loop regulated the ccRCC cell functions via c-Myc mediated EMT process. This study provides a novel regulatory model of circRNA via forming a positive-feedback loop that perpetuates the circESRP1/miR-3942/CTCF axis, suggesting that this signaling may serve as a novel target for the treatment of ccRCC.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop

et al. 2021

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“…Careful mutational analysis of key residues co-ordinating Zn 2+ ion binding and ZF formation have shown key central ZFs that contribute binding to a core consensus site, whilst peripheral ZFs stabilise CTCF binding and bind additional conserved and non-conserved motifs [ 16 ]. Through combinatorial DNA binding and ZF multivalency, CTCF plays diverse roles in transcriptional regulation, including the regulation of alternative splicing (as recently reviewed in [ 17 ]). In its role co-ordinating three-dimensional genome architecture, CTCF has been named the ‘master weaver’ protein [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Structure–function relationships explain CTCF zinc finger mutation phenotypes in cancer

Bailey

Gupta

Metierre

et al. 2021

Cell. Mol. Life Sci.

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CCCTC-binding factor (CTCF) plays fundamental roles in transcriptional regulation and chromatin architecture maintenance. CTCF is also a tumour suppressor frequently mutated in cancer, however, the structural and functional impact of mutations have not been examined. We performed molecular and structural characterisation of five cancer-specific CTCF missense zinc finger (ZF) mutations occurring within key intra- and inter-ZF residues. Functional characterisation of CTCF ZF mutations revealed a complete (L309P, R339W, R377H) or intermediate (R339Q) abrogation as well as an enhancement (G420D) of the anti-proliferative effects of CTCF. DNA binding at select sites was disrupted and transcriptional regulatory activities abrogated. Molecular docking and molecular dynamics confirmed that mutations in residues specifically contacting DNA bases or backbone exhibited loss of DNA binding. However, R339Q and G420D were stabilised by the formation of new primary DNA bonds, contributing to gain-of-function. Our data confirm that a spectrum of loss-, change- and gain-of-function impacts on CTCF zinc fingers are observed in cell growth regulation and gene regulatory activities. Hence, diverse cellular phenotypes of mutant CTCF are clearly explained by examining structure–function relationships.

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“…Thus, CTCF and cohesin have co-essential roles in the context of loop extrusion and in the larger context of effecting long-range chromatin interactions that translate into gene expression. It is also important to note that CTCF has several individual functions independent of its interaction with cohesin, such as DNA binding, RNA Polymerase II elongation, and involvement in splicing ( 27 ), which are outside the scope of this review.…”

Section: D Genome Organization and Regulation Of Gene Transcriptionmentioning

confidence: 99%

Cohesin-Mediated Chromatin Interactions and Autoimmunity

et al. 2022

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Proper physiological functioning of any cell type requires ordered chromatin organization. In this context, cohesin complex performs important functions preventing premature separation of sister chromatids after DNA replication. In partnership with CCCTC-binding factor, it ensures insulator activity to organize enhancers and promoters within regulatory chromatin. Homozygous mutations and dysfunction of individual cohesin proteins are embryonically lethal in humans and mice, which limits in vivo research work to embryonic stem cells and progenitors. Conditional alleles of cohesin complex proteins have been generated to investigate their functional roles in greater detail at later developmental stages. Thus, genome regulation enabled by action of cohesin proteins is potentially crucial in lineage cell development, including immune homeostasis. In this review, we provide current knowledge on the role of cohesin complex in leukocyte maturation and adaptive immunity. Conditional knockout and shRNA-mediated inhibition of individual cohesin proteins in mice demonstrated their importance in haematopoiesis, adipogenesis and inflammation. Notably, these effects occur rather through changes in transcriptional gene regulation than through expected cell cycle defects. This positions cohesin at the crossroad of immune pathways including NF-kB, IL-6, and IFNγ signaling. Cohesin proteins emerged as vital regulators at early developmental stages of thymocytes and B cells and after antigen challenge. Human genome-wide association studies are remarkably concordant with these findings and present associations between cohesin and rheumatoid arthritis, multiple sclerosis and HLA-B27 related chronic inflammatory conditions. Furthermore, bioinformatic prediction based on protein-protein interactions reveal a tight connection between the cohesin complex and immune relevant processes supporting the notion that cohesin will unearth new clues in regulation of autoimmunity.

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CTCF as a regulator of alternative splicing: new tricks for an old player

Cited by 39 publications

References 143 publications

CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop

CircESRP1 inhibits clear cell renal cell carcinoma progression through the CTCF-mediated positive feedback loop

Structure–function relationships explain CTCF zinc finger mutation phenotypes in cancer

Cohesin-Mediated Chromatin Interactions and Autoimmunity

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