title: Hydroxylation of 5-methylcytosine by TET2 maintains the active state of the mammalian HOXA cluster.
abstract: Differentiation is accompanied by extensive epigenomic reprogramming, leading to the repression of stemness factors and the transcriptional maintenance of activated lineage-specific genes. Here we use the mammalian Hoxa cluster of developmental genes as a model system to follow changes in DNA modification patterns during retinoic acid-induced differentiation. We find the inactive cluster to be marked by defined patterns of 5-methylcytosine (5mC). Upon the induction of differentiation, the active anterior part of the cluster becomes increasingly enriched in 5-hydroxymethylcytosine (5hmC), following closely the colinear activation pattern of the gene array, which is paralleled by the reduction of 5mC. Depletion of the 5hmC generating dioxygenase Tet2 impairs the maintenance of Hoxa activity and partially restores 5mC levels. Our results indicate that gene-specific 5mC-5hmC conversion by Tet2 is crucial for the maintenance of active chromatin states at lineage-specific loci.
authors.affiliation: Division of Epigenetics, DKFZ-ZMBH Alliance, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Bocker
authors.forename: Francesca
authors.initials: F
authors.lastname: Tuorto
authors.forename: Günter
authors.initials: G
authors.lastname: Raddatz
authors.forename: Tanja
authors.initials: T
authors.lastname: Musch
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Frank
authors.initials: F
authors.lastname: Lyko
authors.forename: Achim
authors.initials: A
authors.lastname: Breiling
mesh_terms: D044503:5-Methylcytosine / Q000378:metabolism* / Q000031:analogs & derivatives; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003596:Cytosine / Q000031:analogs & derivatives / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D049308:Dioxygenases; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; C011865:5-hydroxymethylcytosine; C088144:HoxA protein; D044503:5-Methylcytosine; D003596:Cytosine; D049308:Dioxygenases; C541081:TET2 protein, human