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

Eric Metzger, Dominica Willmann, Joel McMillan, Ignasi Forne, Philipp Metzger, Stefan Gerhardt, Kerstin Petroll, Anne Von Maessenhausen, Sylvia Urban, Anne Kathrin Schott, Alexsandra Espejo, Adrien Eberlin, Daniel Wohlwend, Katrin M. Schüle, Michael Schleicher, Sven Perner, Mark T. Bedford, Manfred Jung, Jörn Dengjel, Ralf Flaig & 3 others Axel Imhof, Oliver Einsle, Roland Schüle*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)132-139
Number of pages8
JournalNature Structural and Molecular Biology
Volume23
Issue number2
DOIs
Publication statusPublished - 2016
Externally publishedYes

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    Metzger, E., Willmann, D., McMillan, J., Forne, I., Metzger, P., Gerhardt, S., ... Schüle, R. (2016). Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. Nature Structural and Molecular Biology, 23(2), 132-139. https://doi.org/10.1038/nsmb.3153