The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis

Abstract

The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called “Brother of Regulator of Imprinted Sites” (BORIS) or “CTCF-like” (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint.

Zmym4 is required for early cranial gene expression and craniofacial cartilage formation

“…ZMYM3 serves as a scaffolding protein that coordinates interactions between deacetylases, demethylases, and RNase H type enzymes (including HDAC and CoREST), and the eighth and ninth zinc fingers of ZMYM2 protein can bind directly to the LSD1-CoREST-HDAC complex ( Shapson-Coe et al, 2019 ). As RNase H2 can interact with both ZMYM2 and ZMYM4, it has been suggested that ZMYM4 may also interact with the LSD1-CoREST-HDAC complex to mediate transcriptional regulation ( Jabbari et al, 2018 ; Shapson-Coe et al, 2019 ). Furthermore, ZMYM2 and ZMYM3 contain a new class of SUMO-interacting motifs (SIMs) that can interact with SUMO2 in a 1:1 stoichiometry, and recent studies show that ZMYM4 is also SUMOylated ( Anderson, 2015 ; Lamoliatte et al, 2017 ; Cibis et al, 2020 ).…”

Molecular Lesions of Insulator CTCF and Its Paralogue CTCFL (BORIS) in Cancer: An Analysis from Published Genomic Studies

“…In the 10 samples with CTCFL mutations among samples that had complete mutations and copy number alterations information in the Colorectal PanCancer Atlas cohort [15] (Table 5), all had concomitant mutations in one of the four MSI associated genes or the POLE or POLD1 genes, while only one of the 25 samples with CTCFL amplifications (used as a control) had such lesions in MSI-associated genes or POLE / POLD1 genes (in POLD1 ) (Fisher’s two-tailed exact test p < 0.0001). In the respective endometrial carcinoma TCGA PanCancer Atlas study, which included 509 cases with complete mutations and copy number alterations information [23], among the 27 cases with CTCFL mutations 22 had mutations in one of the four MSI associated genes or the POLE or POLD1 genes.…”

“…Thus, CTCFL belongs to the category of so called cancer testis antigens, alternatively termed cancer-germline antigens [14]. Although details of the interaction are not known, CTCFL has been reported to be part of the CTCF interactome [15]. Whether the two proteins interact directly or indirectly in cells where they are co-expressed remains to be confirmed experimentally.…”