title: TET3 is recruited by REST for context-specific hydroxymethylation and induction of gene expression.
abstract: Ten-eleven translocation hydroxylases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In neurons, increased 5hmC levels within gene bodies correlate positively with gene expression. The mechanisms controlling TET activity and 5hmC levels are poorly understood. In particular, it is not known how the neuronal TET3 isoform lacking a DNA-binding domain is targeted to the DNA. To identify factors binding to TET3, we screened for proteins that co-precipitate with TET3 from mouse retina and identified the transcriptional repressor REST as a highly enriched TET3-specific interactor. REST was able to enhance TET3 hydroxylase activity after co-expression and overexpression of TET3-activated transcription of REST target genes. Moreover, we found that TET3 also interacts with NSD3 and two other H3K36 methyltransferases and is able to induce H3K36 trimethylation. We propose a mechanism for transcriptional activation in neurons that involves REST-guided targeting of TET3 to the DNA for directed 5hmC generation and NSD3-mediated H3K36 trimethylation.
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Arshan
authors.initials: A
authors.lastname: Perera
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Eisen
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Mirko
authors.initials: M
authors.lastname: Wagner
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Silvia K
authors.initials: SK
authors.lastname: Laube
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Andrea F
authors.initials: AF
authors.lastname: Künzel
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Koch
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Steinbacher
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Schulze
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Victoria
authors.initials: V
authors.lastname: Splith
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Nana
authors.initials: N
authors.lastname: Mittermeier
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Müller
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Biel
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Chemistry, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: thomas.carell@cup.uni-muenchen.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carell
authors.affiliation: Center for Integrated Protein Science Munich CiPS(M) at the Department of Pharmacy - Center for Drug Research, Ludwig-Maximilians-Universität München, 81377 Munich, Germany. Electronic address: stylianos.michalakis@cup.uni-muenchen.de.
authors.forename: Stylianos
authors.initials: S
authors.lastname: Michalakis
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000818:Animals; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D049308:Dioxygenases; D005786:Gene Expression Regulation; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D012160:Retina / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D000099229:RE1-Silencing Transcription Factor
chemical_list: D044503:5-Methylcytosine; D003596:Cytosine; D004268:DNA-Binding Proteins; D049308:Dioxygenases; D011495:Histone-Lysine N-Methyltransferase; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C011865:5-hydroxymethylcytosine; C551915:Tet3 protein, mouse