title: TET-dependent regulation of retrotransposable elements in mouse embryonic stem cells.
abstract: Ten-eleven translocation (TET) enzymes oxidise DNA methylation as part of an active demethylation pathway. Despite extensive research into the role of TETs in genome regulation, little is known about their effect on transposable elements (TEs), which make up nearly half of the mouse and human genomes. Epigenetic mechanisms controlling TEs have the potential to affect their mobility and to drive the co-adoption of TEs for the benefit of the host.
  
  
  
  We performed a detailed investigation of the role of TET enzymes in the regulation of TEs in mouse embryonic stem cells (ESCs). We find that TET1 and TET2 bind multiple TE classes that harbour a variety of epigenetic signatures indicative of different functional roles. TETs co-bind with pluripotency factors to enhancer-like TEs that interact with highly expressed genes in ESCs whose expression is partly maintained by TET2-mediated DNA demethylation. TETs and 5-hydroxymethylcytosine (5hmC) are also strongly enriched at the 5' UTR of full-length, evolutionarily young LINE-1 elements, a pattern that is conserved in human ESCs. TETs drive LINE-1 demethylation, but surprisingly, LINE-1s are kept repressed through additional TET-dependent activities. We find that the SIN3A co-repressive complex binds to LINE-1s, ensuring their repression in a TET1-dependent manner.
  
  
  
  Our data implicate TET enzymes in the evolutionary dynamics of TEs, both in the context of exaptation processes and of retrotransposition control. The dual role of TET action on LINE-1s may reflect the evolutionary battle between TEs and the host.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, E1 2AT, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: de la Rica
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, E1 2AT, UK.
authors.forename: Özgen
authors.initials: Ö
authors.lastname: Deniz
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, E1 2AT, UK.
authors.forename: Kevin C L
authors.initials: KC
authors.lastname: Cheng
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, E1 2AT, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Todd
authors.affiliation: Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cruz
authors.affiliation: Epigenetics Programme, Babraham Institute, Cambridge, CB22 3AT, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Houseley
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, E1 2AT, UK. m.branco@qmul.ac.uk.
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Branco
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D020084:Long Interspersed Nucleotide Elements / Q000235:genetics; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics; D018626:Retroelements / Q000235:genetics*; D056264:Sin3 Histone Deacetylase and Corepressor Complex
chemical_list: D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D018626:Retroelements; C099683:SIN3A transcription factor; C540839:TET1 protein, mouse; D049308:Dioxygenases; C551914:Tet2 protein, mouse; D056264:Sin3 Histone Deacetylase and Corepressor Complex
keywords: DNA methylation; Embryonic stem cells; Enhancers; Hydroxymethylation; LINE-1; Retrotransposons; Ten-eleven translocation enzymes