Nizialek Emily A, Sankunny Madhav, Niazi Farshad, Eng Charis
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Nucleic Acids Res. 2016 May 5;44(8):3586-94. doi: 10.1093/nar/gkv1481. Epub 2015 Dec 15.
Maintenance of proper chromatin states and genomic stability is vital for normal development and health across a range of organisms. Here, we report on the role of KLLN in maintenance of pericentric H3K9 trimethylation (H3K9me3) and genomic stability. Germline hypermethylation of KLLN, a gene uncovered well after the human genome project, has been linked to Cowden cancer-predisposition syndrome (CS) in PTEN wild-type cases. KLLN first identified as a p53-dependent tumor suppressor gene, was believed to bind randomly to DNA and cause S-phase arrest. Using chromatin immunoprecipitation-based sequencing (ChIP-seq), we demonstrated that KLLN binds to DNA regions enriched with H3K9me3. KLLN overexpression correlated with increased H3K9 methyltransferase activity and increased global H3K9me3, while knockdown of KLLN had an opposite effect. We also found KLLN to localize to pericentric regions, with loss of KLLN resulting in dysregulation of pericentric heterochromatin, with consequent chromosomal instability manifested by increased micronuclei formation and numerical chromosomal aberrations. Interestingly, we show that KLLN interacts with DBC1, with consequent abrogation of DBC1 inhibition of SUV39H1, a H3K9 methyltransferase, suggesting the mode of KLLN regulating H3K9me3. These results suggest a critical role for KLLN as a potential regulator of pericentric heterochromatin formation, genomic stability and gene expression.
维持适当的染色质状态和基因组稳定性对于一系列生物体的正常发育和健康至关重要。在此，我们报告了KLLN在维持着丝粒周围H3K9三甲基化（H3K9me3）和基因组稳定性中的作用。KLLN是人类基因组计划之后才被充分发现的一个基因，其种系高甲基化与PTEN野生型病例中的考登癌症易感综合征（CS）相关。KLLN最初被鉴定为一个p53依赖性肿瘤抑制基因，被认为随机结合DNA并导致S期停滞。利用基于染色质免疫沉淀的测序（ChIP-seq），我们证明KLLN结合到富含H3K9me3的DNA区域。KLLN的过表达与H3K9甲基转移酶活性增加以及整体H3K9me3增加相关，而敲低KLLN则产生相反的效果。我们还发现KLLN定位于着丝粒周围区域，KLLN的缺失导致着丝粒周围异染色质失调，进而表现为微核形成增加和染色体数目畸变，导致染色体不稳定。有趣的是，我们表明KLLN与DBC1相互作用，从而消除了DBC1对H3K9甲基转移酶SUV39H1的抑制作用，提示了KLLN调节H3K9me3的模式。这些结果表明KLLN作为着丝粒周围异染色质形成、基因组稳定性和基因表达的潜在调节因子具有关键作用。
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