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Agenda de l'ENS de Lyon

TET proteins, New Cofactors for Nuclear Receptors

Soutenance de thèse

Jeudi 06 juil 2017
Soutenance de thèse de Mme Wenyue GUAN de l'IGFL sous la direction de Mme Karine GAUTHIER-VANACKER et sous la codirection de M. Jiemin WONG en cotutelle avec l'ECNU


Soutenance de thèse de Mme Wenyue GUAN de l'IGFL sous la direction de Mme Karine GAUTHIER-VANACKER et sous la codirection de M. Jiemin WONG en cotutelle avec l'ECNU

Description générale
–   Thyroid hormone receptors (TRs) belong to the nuclear receptors (NR) superfamily. There are three isoforms TRα1, TRβ1 and TRβ2 that are respectively encoded by the THRA and THRB genes. DNA methylation at the fifth position of cytosine is an important epigenetic modification that affects chromatin structure and gene expression. Recent studies have established a critical function of the Ten-eleven translocation (TET) family proteins in regulating DNA methylation dynamics by converting 5-methyl-cytosine (5mC) into 5-hydroxymethylcytosine (5hmC).
Studies demonstrated that TETs proteins possess catalytic activity dependent and independent transcriptional regulatory functions. Our study reveals a hormone modulated interaction between TR and TET3 observed both by in vitro pull-down assay and in vivo immuno-precipitation assay. The AF2 domain of TR and the catalytic domain and CXXC domain of TET3 are responsible for their interaction. The interaction between TET3 and TR allows the stabilization of TR, its preferential recruitment to the chromatin and thus a potentiation of its transcriptional activity. TET3 was first identified as a DNA hydroxymethylase and demonstrated to reshape the chromatin landscape. However its enzymatic activity is not involved in its ability to regulate TR transcriptional activity.
So this study highlights a new mode of action for TET3 as an unconventional co-regulator of TR modulating its stability/chromatin accessibility rather that its intrinsic transcriptional activity. Interestingly the differential ability of different TRα mutants, relevant for the human RTHα disease, to interact with TET3 might explain their differential dominant negative activity.
This regulatory function of TET3 might be more general towards the nuclear receptor transcriptional factors since an interaction between TET3 and other members of NR family was observed, such as AR (androgen receptor), ERR (Estrogen-related receptor) and RAR (retinoic acid receptor). As for AR, the AR ligand disrupts TET3/AR interaction, and ERR antagonist strengthens ERR/TET3 interaction. However, the interaction between TET3 and RAR seems to be different from all the other ones. Indeed, RAR interact with TET3 independent of retinoic acid, and the interaction area between TET3 and RAR are different from those involved for TR/TET3, here it involves the CXXC & catalytic domain of TET3 and the DNA binding domain of RAR, this difference might partially explain why the hormone treatment acts in different way on the interaction between TET3/TR and TET3/RAR. Furthermore, we observed that TETs’ knocking out severely impaired the expression of a subset of RA response genes in ES cells, suggesting that TET proteins positively regulate RAR activity. We are now working on uncovering the mechanisms underline this regulation. Unlike in the case for TET3/TR, the protein level of RAR is not modulated by TETs knocking out in ES cells; however, TET proteins do facilitate RAR recruitment to chromatin (validated both by ChIP and cell fractionation).
Further experiments need to be done to fully understand the mode of action of TET proteins in regulating RAR activity.

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