title: Cancer-predisposition gene KLLN maintains pericentric H3K9 trimethylation protecting genomic stability.
abstract: 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.
authors.affiliation: 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.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Nizialek
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Madhav
authors.initials: M
authors.lastname: Sankunny
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Farshad
authors.initials: F
authors.lastname: Niazi
authors.affiliation: 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 Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA Germline High Risk Focus Group, CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio 44106, USA engc@ccf.org.
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D006223:Hamartoma Syndrome, Multiple / Q000235:genetics; D006570:Heterochromatin / Q000235:genetics / Q000378:metabolism*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D008780:Methyltransferases / Q000037:antagonists & inhibitors; D009369:Neoplasms / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000037:antagonists & inhibitors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D004268:DNA-Binding Proteins; D006570:Heterochromatin; C554482:KLLN protein, human; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C407843:SUV39H1 protein, human; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase