Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments  [Hi-C and UMI4C]
Epigenetic mechanisms influencing chromatin architecture are key to the spatio-temporal control of transcription. Here we identify ZNF274 as a new regulator of chromosome compartmentalization that silences lineage-specific gene clusters. ZNF274 is a SCAN-bearing member of the Krüppel-associated box (KRAB)-containing zinc finger proteins (KZFPs). Ablation of ZNF274 results in the transcriptional activation of genomic neighbourhoods encompassing, among others, zinc finger and protocadherin-encoding genes, with loss of H3K9me3 repressive mark, altered 3D genome conformation and de novo CTCF binding. In contrast to other factors that have been implicated in chromatin anchoring, ZNF274 is necessary both for transcriptional silencing and nucleolar tethering. While the establishment of silencing depends on the KRAB domain, we demonstrate that the SCAN domain is required to gather ZNF274 complexes at the nucleolus and efficiently spread heterochromatin. Thus, ZNF274 orchestrates the segregation of developmentally regulated gene clusters at nucleoli to allow timely and selective activation of cell-restricted alleles. Overall design: HiC and UMI4C in HEK293T in WT, ZNF274KO conditions