The Evolution of Epigenetic Regulators CTCF and BORIS/CTCFL in Amniotes

Abstract

CTCF is an essential, ubiquitously expressed DNA-binding protein responsible for insulator function, nuclear architecture, and transcriptional control within vertebrates. The gene CTCF was proposed to have duplicated in early mammals, giving rise to a paralogue called “brother of regulator of imprinted sites” (BORIS or CTCFL) with DNA binding capabilities similar to CTCF, but testis-specific expression in humans and mice. CTCF and BORIS have opposite regulatory effects on human cancer-testis genes, the anti-apoptotic BAG1 gene, the insulin-like growth factor 2/H19 imprint control region (IGF2/H19 ICR), and show mutually exclusive expression in humans and mice, suggesting that they are antagonistic epigenetic regulators. We discovered orthologues of BORIS in at least two reptilian species and found traces of its sequence in the chicken genome, implying that the duplication giving rise to BORIS occurred much earlier than previously thought. We analysed the expression of CTCF and BORIS in a range of amniotes by conventional and quantitative PCR. BORIS, as well as CTCF, was found widely expressed in monotremes (platypus) and reptiles (bearded dragon), suggesting redundancy or cooperation between these genes in a common amniote ancestor. However, we discovered that BORIS expression was gonad-specific in marsupials (tammar wallaby) and eutherians (cattle), implying that a functional change occurred in BORIS during the early evolution of therian mammals. Since therians show imprinting of IGF2 but other vertebrate taxa do not, we speculate that CTCF and BORIS evolved specialised functions along with the evolution of imprinting at this and other loci, coinciding with the restriction of BORIS expression to the germline and potential antagonism with CTCF.

Differential decay of parent-of-origin-specific genomic sharing in cystic fibrosis-affected sib pairs maps a paternally imprinted locus to 7q34

“…Even though this consensus binding site is derived from one genomic region only, CTCF is known to act as a universal chromatin insulator, involved in the regulation of monoand biallelically expressed genes. 32 Similarities to this consensus sequence covering at least 11 bp, whereby no gap or mismatch of the aligned sequence was tolerated, were observed at eight positions in the analyzed 7-Mb genomic sequence of NT_079596. Of these eight motifs, seven are located distal to marker no.…”

The chromatin insulator CTCF and the emergence of metazoan diversity

“…The presence of CTCF in vertebrates (11,(18)(19)(20), flies (10,21), and some nematodes (22) suggests that all protostomes and deuterostomes might possess this 11-ZF protein. To investigate this possibility, we searched in public databases for CTCF candidates and determined their orthology to CTCF in a phylogenetic analysis.…”

Replication Timing: Evolution, Nuclear Organization and Relevance for Human Disease

“…A CTCF gene duplication event is believed to have occurred in the amniote ancestor preceding the divergence of reptiles and birds, as they both have functional CTCF, but not its gene paralogue, BORIS (brother of regulator of imprinted sites) (Hore et al, 2008). BORIS has similar DNA binding capabilities to CTCF, but shows antagonistc epigenetic regulation to CTCF, as well as gonad-specific expression in placental and marsupial mammals (Hore et al, 2008).…”

“…A CTCF gene duplication event is believed to have occurred in the amniote ancestor preceding the divergence of reptiles and birds, as they both have functional CTCF, but not its gene paralogue, BORIS (brother of regulator of imprinted sites) (Hore et al, 2008). BORIS has similar DNA binding capabilities to CTCF, but shows antagonistc epigenetic regulation to CTCF, as well as gonad-specific expression in placental and marsupial mammals (Hore et al, 2008). Conversely, BORIS appears to be widely expressed in monotremes and reptiles, indicating that the gene underwent a functional change after the divergence of therian mammals, which is interesting because as yet, there is no evidence that CTCF binding sites exist in the genomes of earlier diverged monotreme mammals (Hore et al, 2008;Weidman et al, 2004).…”

“…BORIS has similar DNA binding capabilities to CTCF, but shows antagonistc epigenetic regulation to CTCF, as well as gonad-specific expression in placental and marsupial mammals (Hore et al, 2008). Conversely, BORIS appears to be widely expressed in monotremes and reptiles, indicating that the gene underwent a functional change after the divergence of therian mammals, which is interesting because as yet, there is no evidence that CTCF binding sites exist in the genomes of earlier diverged monotreme mammals (Hore et al, 2008;Weidman et al, 2004). However, CTCF sites have been observed in the chicken genome which is an earlier-split vertebrate than the monotreme clade, and tied with the evidence that CTCF binding occurs in therian genomes (Baniahmad et al, 1990;Lobanenkov et al, 1990), it is likely that CTCF sites exist in the montreme genome.…”