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; Axel Imhof; Oliver Einsle; Roland Schüle

doi:10.1038/nsmb.3153

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 FlaigAxel Imhof, Oliver Einsle, Roland Schüle^*

^*Corresponding author for this work

Institute of Pathology

73 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 language	English
Journal	Nature Structural and Molecular Biology
Volume	23
Issue number	2
Pages (from-to)	132-139
Number of pages	8
ISSN	1545-9993
DOIs	https://doi.org/10.1038/nsmb.3153
Publication status	Published - 03.02.2016

Funding

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.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Metzger, E., Willmann, D., McMillan, J., Forne, I., Metzger, P., Gerhardt, S., Petroll, K., Von Maessenhausen, A., Urban, S., Schott, A. K., Espejo, A., Eberlin, A., Wohlwend, D., Schüle, K. M., Schleicher, M., Perner, S., Bedford, M. T., Jung, M., Dengjel, J., ... 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

@article{5926de3d52254c039b87cf7b3e9f2007,

title = "Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation",

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.",

author = "Eric Metzger and Dominica Willmann and Joel McMillan and Ignasi Forne and Philipp Metzger and Stefan Gerhardt and Kerstin Petroll and \{Von Maessenhausen\}, Anne and Sylvia Urban and Schott, \{Anne Kathrin\} and Alexsandra Espejo and Adrien Eberlin and Daniel Wohlwend and Sch{\"u}le, \{Katrin M.\} and Michael Schleicher and Sven Perner and Bedford, \{Mark T.\} and Manfred Jung and J{\"o}rn Dengjel and Ralf Flaig and Axel Imhof and Oliver Einsle and Roland Sch{\"u}le",

note = "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. G{\"u}nther, H. Greschik and J.M. M{\"u}ller for helpful discussions. Publisher Copyright: {\textcopyright} 2016 Nature America, Inc. Copyright: Copyright 2016 Elsevier B.V., All rights reserved.",

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Metzger, E, Willmann, D, McMillan, J, Forne, I, Metzger, P, Gerhardt, S, Petroll, K, Von Maessenhausen, A, Urban, S, Schott, AK, Espejo, A, Eberlin, A, Wohlwend, D, Schüle, KM, Schleicher, M, Perner, S, Bedford, MT, Jung, M, Dengjel, J, Flaig, R, Imhof, A, Einsle, O & Schüle, R 2016, 'Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation', Nature Structural and Molecular Biology, vol. 23, no. 2, pp. 132-139. https://doi.org/10.1038/nsmb.3153

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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 - https://www.scopus.com/pages/publications/84956746981

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 -

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

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