TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions
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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2021-02-01
|
| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124721000899 |
| _version_ | 1818926283813289984 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Rebecca Broome |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T02:54:40Z |
| format | Article |
| id | doaj.art-2f967e69b4e24dc196b740e2f994b931 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-20T02:54:40Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-2f967e69b4e24dc196b740e2f994b9312022-12-21T19:55:57ZengElsevierCell Reports2211-12472021-02-01348108776TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regionsRebecca Broome0Igor Chernukhin1Stacey Jamieson2Kamal Kishore3Evangelia K. Papachristou4Shi-Qing Mao5Carmen Gonzalez Tejedo6Areeb Mahtey7Vasiliki Theodorou8Arnoud J. Groen9Clive D’Santos10Shankar Balasubramanian11Anca Madalina Farcas12Rasmus Siersbæk13Jason S. Carroll14Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Merck Sharp & Dohme (UK) Limited, 120 Moorgate, London EC2M 6UR, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKCancer 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, GreeceCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UKCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Bioscience, Oncology R&D, AstraZeneca, Cambridge CB2 0RE, UK; Corresponding authorCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; University of Southern Denmark, Campusvej 55, 5230 Odense M, Denmark; Corresponding authorCancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124721000899TET2estrogen receptorGATA35hmCgene regulationenhancers |
| spellingShingle | 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 TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions Cell Reports TET2 estrogen receptor GATA3 5hmC gene regulation enhancers |
| title | TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions |
| title_full | TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions |
| title_fullStr | TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions |
| title_full_unstemmed | TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions |
| title_short | TET2 is a component of the estrogen receptor complex and controls 5mC to 5hmC conversion at estrogen receptor cis-regulatory regions |
| title_sort | tet2 is a component of the estrogen receptor complex and controls 5mc to 5hmc conversion at estrogen receptor cis regulatory regions |
| topic | TET2 estrogen receptor GATA3 5hmC gene regulation enhancers |
| url | http://www.sciencedirect.com/science/article/pii/S2211124721000899 |
| work_keys_str_mv | AT rebeccabroome tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT igorchernukhin tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT staceyjamieson tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT kamalkishore tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT evangeliakpapachristou tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT shiqingmao tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT carmengonzaleztejedo tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT areebmahtey tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT vasilikitheodorou tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT arnoudjgroen tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT clivedsantos tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT shankarbalasubramanian tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT ancamadalinafarcas tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT rasmussiersbæk tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions AT jasonscarroll tet2isacomponentoftheestrogenreceptorcomplexandcontrols5mcto5hmcconversionatestrogenreceptorcisregulatoryregions |