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Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments

ABSTRACT: Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments

PROVIDER: PRJNA981170 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR24847700_1.fastq.gz	Fastqsanger.gz
	SRR24847700_2.fastq.gz	Fastqsanger.gz
	SRR24847701_1.fastq.gz	Fastqsanger.gz
	SRR24847701_2.fastq.gz	Fastqsanger.gz
	SRR24847702_1.fastq.gz	Fastqsanger.gz

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Clusters of lineage-specific genes are anchored by ZNF274 in repressive perinucleolar compartments [scRNA-seq]

Project description:Long known as the site of ribosome biogenesis, the nucleolus is increasingly recognized for its role in shaping 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 proteins (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 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 NADs 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.

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Project description: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.

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