Metzger, Eric; Willmann, Dominica; McMillan, Joel; Forne, Ignasi; Metzger, Philipp; Gerhardt, Stefan; Petroll, Kerstin; Maessenhausen, Anne von; Urban, Sylvia; Schott, Anne-Kathrin; Espejo, Alexsandra; Eberlin, Adrien; Wohlwend, Daniel; Schüle, Katrin M.; Schleicher, Michael; Perner, Sven; Bedford, Mark T.; Jung, Manfred; Dengjel, Jörn; Flaig, Ralf; Imhof, Axel; Einsle, Oliver; Schüle, Roland (2016): Assembly of methylated KDM1A and CHD1 drives androgen receptor-dependent transcription and translocation. In: Nature Structural & Molecular Biology, Vol. 23, No. 2: pp. 132-139 |
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.
Item Type: | Journal article |
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Faculties: | Medicine |
Subjects: | 600 Technology > 610 Medicine and health |
ISSN: | 1545-9993 |
Language: | English |
ID Code: | 45398 |
Deposited On: | 27. Apr 2018 08:08 |
Last Modified: | 04. Nov 2020 13:21 |
- BASE
- Metzger, Eric
- Willmann, Dominica
- McMillan, Joel
- Forne, Ignasi
- Metzger, Philipp
- Gerhardt, Stefan
- Petroll, Kerstin
- Maessenhausen, Anne von
- Urban, Sylvia
- Schott, Anne-Kathrin
- Espejo, Alexsandra
- Eberlin, Adrien
- Wohlwend, Daniel
- Schüle, Katrin M.
- Schleicher, Michael
- Perner, Sven
- Bedford, Mark T.
- Jung, Manfred
- Dengjel, Jörn
- Flaig, Ralf
- Imhof, Axel
- Einsle, Oliver
- Schüle, Roland
- Google Scholar
- Metzger, Eric
- Willmann, Dominica
- McMillan, Joel
- Forne, Ignasi
- Metzger, Philipp
- Gerhardt, Stefan
- Petroll, Kerstin
- Maessenhausen, Anne von
- Urban, Sylvia
- Schott, Anne-Kathrin
- Espejo, Alexsandra
- Eberlin, Adrien
- Wohlwend, Daniel
- Schüle, Katrin M.
- Schleicher, Michael
- Perner, Sven
- Bedford, Mark T.
- Jung, Manfred
- Dengjel, Jörn
- Flaig, Ralf
- Imhof, Axel
- Einsle, Oliver
- Schüle, Roland