CTCF As a Regulator of Alternative Splicing: New Tricks for an Old Player

Overview

Journal Nucleic Acids Res

Publisher Oxford University Press

Specialty Biochemistry

Date 2021 Jun 28

PMID 34181707

Citations 23

Authors

Adel B Alharbi

Ulf Schmitz

Charles G Bailey

John E J Rasko

Affiliations

Soon will be listed here.

Abstract

Three decades of research have established the CCCTC-binding factor (CTCF) as a ubiquitously expressed chromatin organizing factor and master regulator of gene expression. A new role for CTCF as a regulator of alternative splicing (AS) has now emerged. CTCF has been directly and indirectly linked to the modulation of AS at the individual transcript and at the transcriptome-wide level. The emerging role of CTCF-mediated regulation of AS involves diverse mechanisms; including transcriptional elongation, DNA methylation, chromatin architecture, histone modifications, and regulation of splicing factor expression and assembly. CTCF thereby appears to not only co-ordinate gene expression regulation but contributes to the modulation of transcriptomic complexity. In this review, we highlight previous discoveries regarding the role of CTCF in AS. In addition, we summarize detailed mechanisms by which CTCF mediates AS regulation. We propose opportunities for further research designed to examine the possible fate of CTCF-mediated alternatively spliced genes and associated biological consequences. CTCF has been widely acknowledged as the 'master weaver of the genome'. Given its multiple connections, further characterization of CTCF's emerging role in splicing regulation might extend its functional repertoire towards a 'conductor of the splicing orchestra'.

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References

Luco R, Pan Q, Tominaga K, Blencowe B, Pereira-Smith O, Misteli T . Regulation of alternative splicing by histone modifications. Science. 2010; 327(5968):996-1000. PMC: 2913848. DOI: 10.1126/science.1184208. View

Bailey C, Metierre C, Feng Y, Baidya K, Filippova G, Loukinov D . CTCF Expression is Essential for Somatic Cell Viability and Protection Against Cancer. Int J Mol Sci. 2018; 19(12). PMC: 6321389. DOI: 10.3390/ijms19123832. View

Sams D, Nardone S, Getselter D, Raz D, Tal M, Rayi P . Neuronal CTCF Is Necessary for Basal and Experience-Dependent Gene Regulation, Memory Formation, and Genomic Structure of BDNF and Arc. Cell Rep. 2016; 17(9):2418-2430. DOI: 10.1016/j.celrep.2016.11.004. View

Parelho V, Hadjur S, Spivakov M, Leleu M, Sauer S, Gregson H . Cohesins functionally associate with CTCF on mammalian chromosome arms. Cell. 2008; 132(3):422-33. DOI: 10.1016/j.cell.2008.01.011. View

Montes M, Sanford B, Comiskey D, Chandler D . RNA Splicing and Disease: Animal Models to Therapies. Trends Genet. 2018; 35(1):68-87. PMC: 6339821. DOI: 10.1016/j.tig.2018.10.002. View

Pradeepa M, Sutherland H, Ule J, Grimes G, Bickmore W . Psip1/Ledgf p52 binds methylated histone H3K36 and splicing factors and contributes to the regulation of alternative splicing. PLoS Genet. 2012; 8(5):e1002717. PMC: 3355077. DOI: 10.1371/journal.pgen.1002717. View

Marina R, Sturgill D, Bailly M, Thenoz M, Varma G, Prigge M . TET-catalyzed oxidation of intragenic 5-methylcytosine regulates CTCF-dependent alternative splicing. EMBO J. 2015; 35(3):335-55. PMC: 4741300. DOI: 10.15252/embj.201593235. View

Huang V, Zheng J, Qi Z, Wang J, Place R, Yu J . Ago1 Interacts with RNA polymerase II and binds to the promoters of actively transcribed genes in human cancer cells. PLoS Genet. 2013; 9(9):e1003821. PMC: 3784563. DOI: 10.1371/journal.pgen.1003821. View

Chen H, Tian Y, Shu W, Bo X, Wang S . Comprehensive identification and annotation of cell type-specific and ubiquitous CTCF-binding sites in the human genome. PLoS One. 2012; 7(7):e41374. PMC: 3400636. DOI: 10.1371/journal.pone.0041374. View

10.

Maunakea A, Chepelev I, Cui K, Zhao K . Intragenic DNA methylation modulates alternative splicing by recruiting MeCP2 to promote exon recognition. Cell Res. 2013; 23(11):1256-69. PMC: 3817542. DOI: 10.1038/cr.2013.110. View

11.

Kanduri C, Pant V, Loukinov D, Pugacheva E, Qi C, Wolffe A . Functional association of CTCF with the insulator upstream of the H19 gene is parent of origin-specific and methylation-sensitive. Curr Biol. 2000; 10(14):853-6. DOI: 10.1016/s0960-9822(00)00597-2. View

12.

Zampieri M, Guastafierro T, Calabrese R, Ciccarone F, Bacalini M, Reale A . ADP-ribose polymers localized on Ctcf-Parp1-Dnmt1 complex prevent methylation of Ctcf target sites. Biochem J. 2011; 441(2):645-52. PMC: 3258657. DOI: 10.1042/BJ20111417. View

13.

Tilgner H, Nikolaou C, Althammer S, Sammeth M, Beato M, Valcarcel J . Nucleosome positioning as a determinant of exon recognition. Nat Struct Mol Biol. 2009; 16(9):996-1001. DOI: 10.1038/nsmb.1658. View

14.

Arzate-Mejia R, Recillas-Targa F, Corces V . Developing in 3D: the role of CTCF in cell differentiation. Development. 2018; 145(6). PMC: 5897592. DOI: 10.1242/dev.137729. View

15.

Zlatanova J, Caiafa P . CTCF and its protein partners: divide and rule?. J Cell Sci. 2009; 122(Pt 9):1275-84. DOI: 10.1242/jcs.039990. View

16.

Park E, Pan Z, Zhang Z, Lin L, Xing Y . The Expanding Landscape of Alternative Splicing Variation in Human Populations. Am J Hum Genet. 2018; 102(1):11-26. PMC: 5777382. DOI: 10.1016/j.ajhg.2017.11.002. View

17.

Phillips J, Corces V . CTCF: master weaver of the genome. Cell. 2009; 137(7):1194-211. PMC: 3040116. DOI: 10.1016/j.cell.2009.06.001. View

18.

Ludwig A, Zhang P, Hastert F, Meyer S, Rausch C, Herce H . Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise. Nucleic Acids Res. 2016; 45(5):2438-2457. PMC: 5389475. DOI: 10.1093/nar/gkw1197. View

19.

Ambigapathy G, Zheng Z, Keifer J . Regulation of BDNF chromatin status and promoter accessibility in a neural correlate of associative learning. Epigenetics. 2015; 10(10):981-93. PMC: 5055205. DOI: 10.1080/15592294.2015.1090072. View

20.

Ambigapathy G, Zheng Z, Li W, Keifer J . Identification of a functionally distinct truncated BDNF mRNA splice variant and protein in Trachemys scripta elegans. PLoS One. 2013; 8(6):e67141. PMC: 3692439. DOI: 10.1371/journal.pone.0067141. View