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TET2 is a component of the ER complex and controls 5mC to 5hmC conversion at ER cis-regulatory regions

ABSTRACT: Estrogen receptor-alpha (ER) drives tumour development and metastasis in ER positive (ER+) breast cancer. GATA3 is a transcription factor that has been closely linked to ER function, but the role of GATA3 in ER-transcriptional activity is not clear. We sought to identify the contribution of GATA3 to the ER complex, by conducting quantitative multiplexed rapid immunoprecipitation mass spectrometry of endogenous proteins (qPLEX-RIME), to assess changes to the ER complex in response to GATA3 depletion. Unexpectedly, very few proteins were dissociated from the ER complex in the absence of GATA3, with the only major change being loss of TET2 in the ER complex. In breast cancer cells and Patient-Derived Xenograft (PDX) tissue, TET2 binding events were shown to constitute a near-total subset of ER binding events, and loss of TET2 was functionally associated with reduced activation of proliferative pathways. To investigate the TET2-ER relationship, the role of TET2 in regulating DNA modifications in ER+ breast cancer cells was examined. TET2 knockdown did not appear to result in changes to global DNA methylation, however, oxidation of methylated DNA to 5-hydroxymethylcytosine (5hmC) was significantly reduced after TET2 depletion and these events occurred at ER enhancers. These findings implicate TET2 in the production and maintenance of 5hmC at ER sites, providing a potential mechanism for TET2-mediated regulation of ER target genes.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Breast

DISEASE(S): Breast Cancer

SUBMITTER: Evangelia Papachristou

LAB HEAD: Jason Carroll

PROVIDER: PXD019438 | Pride | 2021-02-10

REPOSITORIES: Pride

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			Action	DRS
	RIME_ER_Rep1.msf	Msf
	RIME_ER_Rep2.msf	Msf
	RIME_ER_Rep3.msf	Msf
	RIME_ER_rep01.raw	Raw
	RIME_ER_rep02.raw	Raw

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TET2 is a component of the ER complex and controls 5mC to 5hmC conversion at ER cis-regulatory regions [MMS/RRHP]

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