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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234312 | GEO | 2024/09/17

REPOSITORIES: GEO

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Project description:Only a small percentage of human transcription factors (e.g. those associated with a specific differentiation program) are expressed in a given cell type. Thus, cell fate is mainly determined by cell type-specific silencing of transcription factors that drive different cellular lineages. Several histone modifications have been associated with gene silencing, including H3K27me3 and H3K9me3. We have previously shown that the two largest classes of mammalian transcription factors are marked by distinct histone modifications; homeobox genes are marked by H3K27me3 and zinc finger genes are marked by H3K9me3. Several histone methyltransferases (e.g. G9a and SETDB1) may be involved in mediating the H3K9me3 silencing mark. We have used ChIP-chip (GSE24480) and ChIP-seq to demonstrate that SETDB1, but not G9a, is associated with regions of the genome enriched for H3K9me3. A current model is that SETDB1 is recruited to specific genomic locations via interaction with the corepressor TRIM28 (KAP1), which is in turn recruited to the genome via interaction with zinc finger transcription factors that contain a Kruppel-associated box (KRAB) domain. However, specific KRAB-ZNFs that recruit TRIM28 (KAP1) and SETDB1 to the genome have not been identified. We now show that ZNF274 (a KRAB-ZNF that contains 5 C2H2 zinc finger domains), can interact with KAP1 in vitro and, using ChIP-seq, we show that ZNF274 binding sites co-localize with SETDB1, KAP1, and H3K9me3 at the 3’ ends of zinc finger genes. Knockdown of ZNF274 with siRNAs reduced the levels of KAP1 and SETDB1 recruitment to the binding sites. These studies provide the first identification of a KRAB domain-containing ZNFs that is involved in recruitment of the KAP1 and SETDB1 to the human genome. For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf 7 total ChIP-seq datasets; 4 ZNF274 datasets done in duplicate from 4 different cell lines; 1 KAP1 duplicate dataset done in duplicate from K562 cells; 1 SetDB1 duplicate dataset from K562 cells; 1 H3K9me3 duplicate dataset from K562 cells

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

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