Long known as the site of ribosome biogenesis, the nucleolus is increasingly recognized for its role in shaping three-dimensional (3D) genome organization. Still, the mechanisms governing the targeting of selected regions of the genome to nucleolus-associated domains (NADs) remain enigmatic. Here, we reveal the essential role of ZNF274, a SCAN-bearing member of the Krüppel-associated box (KRAB)–containing zinc finger protein (KZFP) family, in sequestering lineage-specific gene clusters within NADs. Ablation of ZNF274 triggers transcriptional activation across entire genomic neighborhoods—encompassing, among others, protocadherin and KZFP-encoding genes—with loss of repressive chromatin marks, altered the 3D genome architecture and de novo CTCF binding. Mechanistically, ZNF274 anchors target DNA sequences at the nucleolus and facilitates their compartmentalization via a previously uncharted function of the SCAN domain. Our findings illuminate the mechanisms underlying NAD organization and suggest that perinucleolar entrapment into repressive hubs constrains the activation of tandemly arrayed genes to enable selective expression and modulate cell differentiation programs during development.

中文翻译：

---

谱系特异性基因簇由 ZNF274 锚定在抑制性核仁周围区室


核仁长期以来一直被称为核糖体生物发生位点，因其在塑造三维 （3D） 基因组组织中的作用而日益得到认可。尽管如此，控制基因组选定区域靶向核仁相关结构域 （NAD） 的机制仍然是个谜。在这里，我们揭示了 ZNF274 的重要作用，ZNF274 是含 Krüppel 相关盒 （KRAB） 的锌指蛋白 （KZFP） 家族的 SCAN 携带成员，在隔离 NAD 内的谱系特异性基因簇中的作用。ZNF274 的消融触发整个基因组邻域的转录激活，其中包括原钙粘蛋白和 KZFP 编码基因，抑制性染色质标记丢失，改变了 3D 基因组结构和从头 CTCF 结合。从机制上讲，ZNF274 将靶 DNA 序列锚定在核仁上，并通过 SCAN 结构域以前未知的功能促进它们的区室化。我们的研究结果阐明了 NAD 组织的潜在机制，并表明核仁周围包埋到抑制性枢纽中限制了串联排列基因的激活，从而在发育过程中实现选择性表达和调节细胞分化程序。