A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing

• Published in: Nature communications Vol. 9; no. 1; pp. 1683 - 13
• Main Authors: Kato, Masaki, Takemoto, Keiko, Shinkai, Yoichi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 27.04.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Cell Differentiation - physiology; Derepression; DNA (Cytosine-5-)-Methyltransferase 1 - genetics; DNA (Cytosine-5-)-Methyltransferase 1 - metabolism; DNA Methylation - physiology; DNMT1 protein; Embryo cells; Embryo fibroblasts; Endogenous retroviruses; Endogenous Retroviruses - physiology; Epigenetic Repression - physiology; Fibroblasts; Genes, Intracisternal A-Particle - genetics; Histone H3; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Histones - genetics; Host-Pathogen Interactions - genetics; Lysine; Mice; Mice, Knockout; Mouse Embryonic Stem Cells; Somatic cells; Stem cell transplantation; Stem cells; Transcription factors; Virus Activation - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-04132-9

Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. Here we find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell-type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification.