Table 1.
Summary of the known mechanisms of CTCF in modulating alternative splicing. CTCF-mediated AS regulatory mechanisms are divided into verified or putative roles
| Mechanism | Context | Model | Description | Biological relevance | Ref |
|---|---|---|---|---|---|
| Verified mechanisms | |||||
| RNAPII elongation* | CD45 | Human Burkitt lymphoma B cells | CTCF binding to CD45 exon 5 promotes exon inclusion via stalling RNAPII elongation | Lymphocyte development | (33,34) |
| RNAPII elongation | PUMA, p21 | Human HCT116 colorectal carcinoma cells | CTCF binding recruits cohesin downstream to PUMA and p21 promoters, which stalls RNAPII elongation and regulates their expression | p53-mediated apoptotic response | (35) |
| DNA methylation | BDNF | Turtle brain tissue, mouse embryonic cortical neurons | CTCF binding to unmethylated target sites proximal to BDNF promotes canonical BDNF splicing | Learning-dependent activities | (38,39) |
| DNA methylation | Cacna1b | F11 (rat dorsal-root ganglion neurons/mouse neuroblastoma hybrid) cells | CTCF binding to hypomethylated sites at Cacna1b promotes mutually exclusive exons | Calcium ion channel plasticity | (41) |
| Chromatin architecture* | Pcdh | Human SK-N-SH and mouse N2a neuroblastoma cells, mouse CAD catecholaminergic neuronal tumor cells | CTCF/cohesin-mediated DNA looping induces alternatively spliced Pcdh isoforms | Neuronal cell surface diversity | (36,37) |
| Chromatin architecture* | Multiple transcripts | Human HCT116 colorectal carcinoma cells | CTCF/cohesin-mediated DNA looping induces alternative polyadenylation | Altering cancer transcriptome | (40) |
| Splicing factor recruitment | c-myc, U2 snRNA | HeLa cells | CTCF controls RNAPII elongation and termination via recruitment of NELF, DSIF and P-TEFb | Gene expression | (42) |
| Putative mechanisms | |||||
| RNAPII elongation | Genome-wide | Human Burkitt lymphoma B cells | Association between CTCF and RNAPII elongation proximal to included exons | - | (33,34) |
| RNAPII elongation | Genome-wide | Various cells | Association between CTCF binding and RNAPII stalling at specific sites | - | (58,59) |
| DNA methylation | Genome-wide | Mouse retina and brain tissues | Association of CTCF binding sites and DNA methylation in alternatively spliced transcripts | - | (43) |
| Chromatin architecture* | Genome-wide | Human lymphoblastoid cells | CTCF-mediated chromatin loops bring alternatively spliced exons into physical proximity of gene promoter | - | (44) |
| DNA methylation | Genome-wide | Mouse brain, kidney, liver, muscle and spleen tissues | Ctcf haploinsufficiency mediates tissue-specific changes in AS events, notably an increase in intron retention in Ctcf haploinsufficient liver and kidney | - | (45) |
| Histone modification | Genome-wide | Various cells | Association between CTCF binding and histone modifications close to alternatively spliced exons | - | (35,46,129) |
| Miscellaneous | Genome-wide | Human MCF7 breast cancer cells Non-tumorigenic MCF10A mammary cells | Association between CTCF and HP1α proximal to included exons which may involve splicing factor recruitment | - | (46) |
| Miscellaneous* | Genome-wide | Various cells | CTCF-mediated activation of PARP1 and PARylation govern AS via hypomethylation of CTCF binding sites, RNAPII elongation, chromatin relaxation and splicing factor recruitment | - | (60,61,66–69) |
*denotes involvement of methylation-regulated CTCF sites.