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

作者：Metzger Eric; Willmann Dominica; McMillan Joel; Forne Ignasi; Metzger Philipp; Gerhardt Stefan; Petroll Kerstin; von Maessenhausen Anne; Urban Sylvia; Schott Anne Kathrin; Espejo Alexsandra; Eberlin Adrien; Wohlwend Daniel; Schuele Katrin M; Schleicher Michael; Perner Sven; Bedford Mark T; Jung Manfred; Dengjel Joern; Flaig Ralf; Imhof Axel; Einsle Oliver; Schuele Roland

来源：Nature Structural & Molecular Biology, 2016, 23(2): 132-+.

DOI：10.1038/nsmb.3153

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.

• 出版日期2016-2