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Assembly of methylated KDM1A and CHD1 drives androgen receptor–dependent transcription and translocation

DOI: 10.1038/nsmb.3153 DOI Help
PMID: 26751641 PMID Help

Authors: Eric Metzger (Klinikum der Universität Freiburg) , Dominica Willmann (Klinikum der Universität Freiburg) , Joel Mcmillan (Diamond Light Source; Klinikum der Universität Freiburg) , Ignasi Forne (University of Munich) , Philipp Metzger (Klinikum der Universität Freiburg) , Stefan Gerhardt (Albert-Ludwigs-Universität Freiburg) , Kerstin Petroll (Klinikum der Universität Freiburg) , Anne Von Maessenhausen (University Hospital of Luebeck and Leibniz Research Center) , Sylvia Urban (Klinikum der Universität Freiburg) , Anne-kathrin Schott (Klinikum der Universität Freiburg) , Alexsandra Espejo (University of Texas) , Adrien Eberlin (Klinikum der Universität Freiburg) , Daniel Wohlwend (Albert-Ludwigs-Universität Freiburg) , Katrin M Schüle (Klinikum der Universität Freiburg) , Michael Schleicher (Boehringer Ingelheim) , Sven Perner (University Hospital of Luebeck and Leibniz Research Center) , Mark T Bedford (University of Texas) , Manfred Jung (Deutsches Konsortium für Translationale Krebsforschung) , Jörn Dengjel (Center for Biological Systems Analysis, Freiburg) , Ralf Flaig (Diamond Light Source) , Axel Imhop (University of Munich) , Oliver Einsle (Albert-Ludwigs-Universität Freiburg) , Roland Schule (Klinikum der Universität Freiburg)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Structural & Molecular Biology

State: Published (Approved)
Published: January 2016

Abstract: Prostate cancer evolution is driven by a combination of epigenetic and genetic alterations such as coordinated chromosomal rearrangements, termed chromoplexy. TMPRSS2-ERG gene fusions found in human prostate tumors are a hallmark of chromoplexy. TMPRSS2-ERG fusions have been linked to androgen signaling and depend on androgen receptor (AR)-coupled gene transcription. Here, we show that dimethylation of KDM1A at K114 (to form K114me2) by the histone methyltransferase EHMT2 is a key event controlling androgen-dependent gene transcription and TMPRSS2-ERG fusion. We identified CHD1 as a KDM1A K114me2 reader and characterized the KDM1A K114me2–CHD1 recognition mode by solving the cocrystal structure. Genome-wide analyses revealed chromatin colocalization of KDM1A K114me2, CHD1 and AR in prostate tumor cells. Together, our data link the assembly of methylated KDM1A and CHD1 with AR-dependent transcription and genomic translocations, thereby providing mechanistic insight into the formation of TMPRSS2-ERG gene fusions during prostate-tumor evolution

Keywords: Prostate cancer; Methylation; X-ray crystallography

Subject Areas: Biology and Bio-materials


Beamlines: I04-Macromolecular Crystallography

Other Synchrotrons: Swiss Light Source