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Abstract
5-methylcytosine (5mC) is an epigenetic modification associated with repression of transcription. 5mC (DNA methylation) is highly enriched at repetitive sequences including pericentromeric satellite repeats that surround chromosome centromeres. Loss of DNA methylation at these repeats is seen in aging, cancer, and in the rare autosomal recessive disease Immunodeficiency, Centromere Instability, and Facial Anomalies (ICF) syndrome. To date the mechanisms that regulate DNA methylation at pericentromeric repeats remain unclear and we have a limited knowledge of how a loss of DNA methylation at pericentromeric satellite repeats contributes to disease pathology. Homozygous loss-of-function mutations in cell division cycle associated 7 (CDCA7) and zinc finger and BTB domain containing 24 (ZBTB24) have been identified in patients with ICF syndrome. However, the functions of these genes in the regulation of DNA methylation remain unclear. To address this deficiency, our laboratory has developed animal models of ICF syndrome by deleting the zebrafish orthologs of each gene. Homozygous deletion of either zbtb24 or cdca7a results in a specific loss of DNA methylation at pericentromeric repeats similar to that observed in patients with ICF syndrome. However, while zbtb24∆/∆ animals recapitulate most phenotypic hallmarks of ICF syndrome, cdca7a∆/∆ mutants only exhibit a subset of these phenotypes. This finding suggests not all ICF phenotypes are linked to pericentromeric hypomethylation. Mechanistically, we find that zbtb24∆/∆ and cdca7a∆/∆ mutants both show increasingly severe DNA methylation loss at pericentromeres in progressively older animals, suggesting these genes are involved in the long-term maintenance of DNA methylation at pericentromeric satellite repeats.