title: SMYD5 regulates H4K20me3-marked heterochromatin to safeguard ES cell self-renewal and prevent spurious differentiation.
abstract: Epigenetic regulation of chromatin states is thought to control the self-renewal and differentiation of embryonic stem (ES) cells. However, the roles of repressive histone modifications such as trimethylated histone 4 lysine 20 (H4K20me3) in pluripotency and development are largely unknown.
  
  
  
  Here, we show that the histone lysine methyltransferase SMYD5 mediates H4K20me3 at heterochromatin regions. Depletion of SMYD5 leads to compromised self-renewal, including dysregulated expression of OCT4 targets, and perturbed differentiation. SMYD5-bound regions are enriched with repetitive DNA elements. Knockdown of SMYD5 results in a global decrease of H4K20me3 levels, a redistribution of heterochromatin constituents including H3K9me3/2, G9a, and HP1α, and de-repression of endogenous retroelements. A loss of SMYD5-dependent silencing of heterochromatin nearby genic regions leads to upregulated expression of lineage-specific genes, thus contributing to the decreased self-renewal and perturbed differentiation of SMYD5-depleted ES cells.
  
  
  
  Altogether, these findings implicate a role for SMYD5 in regulating ES cell self-renewal and H4K20me3-marked heterochromatin.
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, MI USA.|Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI USA.|Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Kidder
authors.affiliation: Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
authors.forename: Gangqing
authors.initials: G
authors.lastname: Hu
authors.affiliation: Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
authors.forename: Kairong
authors.initials: K
authors.lastname: Cui
authors.affiliation: Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD USA.
authors.forename: Keji
authors.initials: K
authors.lastname: Zhao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D000066673:Cell Self Renewal / Q000502:physiology*; D047369:Chromatin Immunoprecipitation; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry / Q000378:metabolism; D019175:DNA Methylation; D058732:Embryoid Bodies / Q000378:metabolism / Q000473:pathology; D006570:Heterochromatin / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D020071:Interspersed Repetitive Sequences / Q000235:genetics; D008780:Methyltransferases; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013724:Teratoma / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D000090266:Chromobox Protein Homolog 5; D008780:Methyltransferases; C000626075:Smyd5 protein, mouse; D011495:Histone-Lysine N-Methyltransferase
keywords: ChIP-Seq; Chromatin; Differentiation; Embryoid body; Embryonic stem cells; Epigenetics; Gene expression; Genomics; H4K20me3; Heterochromatin; Histone methyltransferase; LINE; LTR; Pluripotent; RNA-Seq; Repetitive DNA; SMYD5; Self-renewal