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首页> 外文期刊>Epigenetics: official journal of the DNA Methylation Society >ATRX binds to atypical chromatin domains at the 3 ' exons of zinc finger genes to preserve H3K9me3 enrichment
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ATRX binds to atypical chromatin domains at the 3 ' exons of zinc finger genes to preserve H3K9me3 enrichment

机译：ATRX与锌指基因3'外显子上的非典型染色质结构域结合以保留H3K9me3富集

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摘要

ATRX is a SWI/SNF chromatin remodeler proposed to govern genomic stability through the regulation of repetitive sequences, such as rDNA, retrotransposons, and pericentromeric and telomeric repeats. However, few direct ATRX target genes have been identified and high-throughput genomic approaches are currently lacking for ATRX. Here we present a comprehensive ChIP-sequencing study of ATRX in multiple human cell lines, in which we identify the 3' exons of zinc finger genes (ZNFs) as a new class of ATRX targets. These 3' exonic regions encode the zinc finger motifs, which can range from 1-40 copies per ZNF gene and share large stretches of sequence similarity. These regions often contain an atypical chromatin signature: they are transcriptionally active, contain high levels of H3K36me3, and are paradoxically enriched in H3K9me3. We find that these ZNF 3' exons are co-occupied by SETDB1, TRIM28, and ZNF274, which form a complex with ATRX. CRISPR/Cas9-mediated loss-of-function studies demonstrate (i) a reduction of H3K9me3 at the ZNF 3' exons in the absence of ATRX and ZNF274 and, (ii) H3K9me3 levels at atypical chromatin regions are particularly sensitive to ATRX loss compared to other H3K9me3-occupied regions. As a consequence of ATRX or ZNF274 depletion, cells with reduced levels of H3K9me3 show increased levels of DNA damage, suggesting that ATRX binds to the 3' exons of ZNFs to maintain their genomic stability through preservation of H3K9me3.
机译：ATRX是一种SWI / SNF染色质重塑剂，被提议通过调控重复序列（如rDNA，反转录转座子以及着丝粒和端粒重复序列）来控制基因组稳定性。然而，很少有直接的ATRX靶基因被鉴定出来，目前ATRX缺乏高通量的基因组方法。在这里，我们介绍了在多种人类细胞系中进行ATRX的全面ChIP测序研究，其中我们将锌指基因（ZNFs）的3'外显子鉴定为ATRX的新型靶标。这些3'外显子区域编码锌指基序，每个ZNF基因的范围为1-40个拷贝，并具有较大的序列相似性。这些区域通常包含非典型的染色质特征：它们具有转录活性，包含高水平的H3K36me3，并且矛盾地富含H3K9me3。我们发现这些ZNF 3'外显子被SETDB1，TRIM28和ZNF274共同占据，它们与ATRX形成复合体。 CRISPR / Cas9介导的功能丧失研究证明（i）在不存在ATRX和ZNF274的情况下ZNF 3'外显子处的H3K9me3减少，并且（ii）与非典型染色质区域相比，H3K9me3水平对ATRX损失特别敏感到其他H3K9me3占领区。由于ATRX或ZNF274耗竭，H3K9me3水平降低的细胞显示出更高的DNA损伤水平，这表明ATRX与ZNFs的3'外显子结合以通过保存H3K9me3来维持其基因组稳定性。

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