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Life Sci Alliance. 2018 Sep 19;1(5):e201800117. doi: 10.26508/lsa.201800117. eCollection 2018 Oct.

CARM1 methylates MED12 to regulate its RNA-binding ability.

Author information

1
Department of Epigenetics and Molecular Carcinogenesis, MD Anderson Cancer Center, The University of Texas, Smithville, TX, USA.
2
Cell Signaling Technology Inc., Danvers, MA, USA.
3
Department of Cancer Genetics and Epigenetics, Beckman Research Institute at City of Hope, Duarte, CA, USA.
4
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
5
Center for Precision Environmental Health, Baylor College of Medicine, Houston, TX, USA.
6
Department of Molecular Medicine, Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

Abstract

The coactivator-associated arginine methyltransferase (CARM1) functions as a regulator of transcription by methylating a diverse array of substrates. To broaden our understanding of CARM1's mechanistic actions, we sought to identify additional substrates for this enzyme. To do this, we generated CARM1 substrate motif antibodies, and used immunoprecipitation coupled with mass spectrometry to identify cellular targets of CARM1, including mediator complex subunit 12 (MED12) and the lysine methyltransferase KMT2D. Both of these proteins are implicated in enhancer function. We identified the major CARM1-mediated MED12 methylation site as arginine 1899 (R1899), which interacts with the Tudor domain-containing effector molecule, TDRD3. Chromatin immunoprecipitation-seq studies revealed that CARM1 and the methyl mark it deposits are tightly associated with ERα-specific enhancers and positively modulate transcription of estrogen-regulated genes. In addition, we showed that the methylation of MED12, at the R1899 site, and the recruitment of TDRD3 by this methylated motif are critical for the ability of MED12 to interact with activating noncoding RNAs.

Conflict of interest statement

MT Bedford is a cofounder of EpiCypher. Other authors declare that they have no conflict of interest. Deep sequencing data has been submitted to the NCBI–GEO accession number: GSE72848.

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