TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions
Rebecca Broome,
Igor Chernukhin,
Stacey Jamieson,
Kamal Kishore,
Evangelia K. Papachristou,
Shi-Qing Mao,
Carmen Gonzalez Tejedo,
Areeb Mahtey,
Vasiliki Theodorou,
Arnoud J. Groen,
Clive D’Santos,
Shankar Balasubramanian,
Anca Madalina Farcas,
Rasmus Siersbæk,
Jason S. Carroll
Affiliations
Rebecca Broome
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Igor Chernukhin
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Stacey Jamieson
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Merck Sharp & Dohme (UK) Limited, 120 Moorgate, London EC2M 6UR, UK
Kamal Kishore
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Evangelia K. Papachristou
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Shi-Qing Mao
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Carmen Gonzalez Tejedo
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Areeb Mahtey
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Vasiliki Theodorou
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology – Hellas Nikolaou Plastira 100, 70013 Heraklion, Crete, Greece
Arnoud J. Groen
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Clive D’Santos
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
Shankar Balasubramanian
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
Anca Madalina Farcas
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0RE, UK; Corresponding author
Rasmus Siersbæk
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; Corresponding author
Jason S. Carroll
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Corresponding author
Summary: Estrogen receptor-α (ER) drives tumor development in ER-positive (ER+) breast cancer. The transcription factor GATA3 has been closely linked to ER function, but its precise role in this setting remains unclear. Quantitative proteomics was used to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, few proteins were lost from the ER complex in the absence of GATA3, with the only major change being depletion of the dioxygenase TET2. TET2 binding constituted a near-total subset of ER binding in multiple breast cancer models, with loss of TET2 associated with reduced activation of proliferative pathways. TET2 knockdown did not appear to change global methylated cytosine (5mC) levels; however, oxidation of 5mC to 5-hydroxymethylcytosine (5hmC) was significantly reduced, and these events occurred at ER enhancers. These findings implicate TET2 in the maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.
