ZBTB24, a gene associated with human ICF syndrome, regulates centromeric and pericentrameric heterochromatin formation. ZBTB24

The protein encoded by ZBTB24 belongs to POZ/BTB domain containing zinc finger family. Biallelic mutations in ZBTB24 are known to cause human ICF syndrome with defect in centromeric and pericentromeric heterochromatin. However, it remains unclear whether and how ZBTB24 could directly regulate heterochromatin formation at centromeric and pericentromeric regions. Here we used ChIP-seq to globally identify DNA binding sites of ZBTB24 and observed enriched ZBTB24 binding in the vicinity of centromere. Further loss-of-function experiments provided evidence for the function of ZBTB24 in centromeric and pericentromeric heterochromatic formation. Moreover, we identified TRIM28 as a ZBTB24 interaction partner, a protein previously known to function as a scaffold protein in regulating facultative heterochromatin formation. Finally, we could validate the functional relevance of the interaction between the two proteins and demonstrate their synergistic effect in regulating heterochromatin formation at centromeric and pericentromeric regions, particularly at those containing Sat2/3 repeats.