TY - JOUR
T1 - Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation
AU - Metzger, Eric
AU - Willmann, Dominica
AU - McMillan, Joel
AU - Forne, Ignasi
AU - Metzger, Philipp
AU - Gerhardt, Stefan
AU - Petroll, Kerstin
AU - Von Maessenhausen, Anne
AU - Urban, Sylvia
AU - Schott, Anne Kathrin
AU - Espejo, Alexsandra
AU - Eberlin, Adrien
AU - Wohlwend, Daniel
AU - Schüle, Katrin M.
AU - Schleicher, Michael
AU - Perner, Sven
AU - Bedford, Mark T.
AU - Jung, Manfred
AU - Dengjel, Jörn
AU - Flaig, Ralf
AU - Imhof, Axel
AU - Einsle, Oliver
AU - Schüle, Roland
N1 - Funding Information:
We thank Y. Shinkai (Institute for Virus research, Kyoto University, Japan) for providing reagents. We are obliged to D. Hassan, J. Kappel, A. Rieder, B. Diedrich and O. Schilling for providing excellent technical assistance. We are obliged to T. Günther, H. Greschik and J.M. Müller for helpful discussions.
Publisher Copyright:
© 2016 Nature America, Inc.
Copyright:
Copyright 2016 Elsevier B.V., All rights reserved.
PY - 2016/2/3
Y1 - 2016/2/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84956746981&partnerID=8YFLogxK
U2 - 10.1038/nsmb.3153
DO - 10.1038/nsmb.3153
M3 - Journal articles
C2 - 26751641
AN - SCOPUS:84956746981
SN - 1545-9993
VL - 23
SP - 132
EP - 139
JO - Nature Structural and Molecular Biology
JF - Nature Structural and Molecular Biology
IS - 2
ER -