SMYD5 Controls Heterochromatin and Chromosome Integrity during Embryonic Stem Cell Differentiation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (23), p.6729-6745
• Main Authors: Kidder, Benjamin L, He, Runsheng, Wangsa, Darawalee, Padilla-Nash, Hesed M, Bernardo, M Margarida, Sheng, Shijie, Ried, Thomas, Zhao, Keji
• Format: Article
• Language: English
• Subjects: A549 Cells; Animals; Base Sequence; Cancer; Cell differentiation; Cell Differentiation - genetics; Cell Line, Tumor; Chromatin; Chromosome aberrations; Chromosomes - physiology; Colon; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Deoxyribonucleic acid; Depletion; Derepression; DNA; DNA Copy Number Variations - genetics; Embryo cells; Embryonic Stem Cells - cytology; Epigenesis, Genetic; Gene expression; Genomes; Genomic instability; HCT116 Cells; Heterochromatin; Heterochromatin - physiology; Histone Code - genetics; Histones - metabolism; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lysine; MCF-7 Cells; Methylation; Methyltransferases - genetics; Mice; RNA Interference; RNA, Small Interfering - genetics; Sequence Analysis, DNA; Stem cell transplantation; Stem cells; Transformed cells; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0828

Epigenetic regulation of chromatin states is thought to control gene expression programs during lineage specification. However, the roles of repressive histone modifications, such as trimethylated histone lysine 20 (H4K20me3), in development and genome stability are largely unknown. Here, we show that depletion of SET and MYND domain-containing protein 5 (SMYD5), which mediates H4K20me3, leads to genome-wide decreases in H4K20me3 and H3K9me3 levels and derepression of endogenous LTR- and LINE-repetitive DNA elements during differentiation of mouse embryonic stem cells. SMYD5 depletion resulted in chromosomal aberrations and the formation of transformed cells that exhibited decreased H4K20me3 and H3K9me3 levels and an expression signature consistent with multiple human cancers. Moreover, dysregulated gene expression in SMYD5 cancer cells was associated with LTR and endogenous retrovirus elements and decreased H4K20me3. In addition, depletion of SMYD5 in human colon and lung cancer cells results in increased tumor growth and upregulation of genes overexpressed in colon and lung cancers, respectively. These findings implicate an important role for SMYD5 in maintaining chromosome integrity by regulating heterochromatin and repressing endogenous repetitive DNA elements during differentiation. .