Methylcytosine dioxygenase TET3 interacts with thyroid hormone nuclear receptors and stabilizes their association to chromatin

Abstract

Thyroid hormone receptors (TRs) are members of the nuclear hormone receptor superfamily that act as ligand-dependent transcription factors. Here we identified the ten-eleven translocation protein 3 (TET3) as a TR interacting protein increasing cell sensitivity to T3. The interaction between TET3 and TRs is independent of TET3 catalytic activity and specifically allows the stabilization of TRs on chromatin. We provide evidence that TET3 is required for TR stability, efficient binding of target genes, and transcriptional activation. Interestingly, the differential ability of different TRα1 mutants to interact with TET3 might explain their differential dominant activity in patients carrying TR germline mutations. So this study evidences a mode of action for TET3 as a nonclassical coregulator of TRs, modulating its stability and access to chromatin, rather than its intrinsic transcriptional activity. This regulatory function might be more general toward nuclear receptors. Indeed, TET3 interacts with different members of the superfamily and also enhances their association to chromatin.thyroid hormone receptor | methylcytosine dioxygenase TET3 | protein stability | chromatin recruitment | RTH syndrome T hyroid hormone (T3) is the main natural iodinated compound possessing a biological activity. It exerts a pleiotropic action on development and homeostasis, acting on most, if not all, cell types (1). T3 acts directly on gene transcription by binding to the thyroid hormone receptors (TRs) TRα1, TRβ1, and TRβ2. They are, respectively, encoded by the THRA and THRB genes. In humans, mutations of either THRA or THRB cause the resistance to thyroid hormone syndrome (RTH). The severity of the disease is determined by the precise location of the mutation (2), dictating the ability of the mutated TR to respond to T3 (3).TRs, as the other members of the nuclear receptor superfamily, are ligand-regulated transcription factors consisting of three major functional domains: the amino-terminal A/B domain, the DNAbinding domain, and the ligand-binding domain. TRs can bind to DNA on a TR response element (TRE) the in absence of T3, and on most genes they repress transcription until T3 binds and leads to activation. Helix12 is the major structural element associated with this process. T3 triggers a dramatic shift of its position, leading to dissociation of corepressors and recruitment of coactivators, including coactivators that have the ability to change the chromatin microenvironment (4). T3 binding also induces a rapid proteasomemediated degradation of TRs that is associated with T3-dependent transcriptional activity (5). TR availability and chromatin access are thus possibly important levels of modulation of T3 cellular response.The goal of the present study was to identify epigenetic regulators that interact with, and therefore may modulate, TR transcriptional activity, using in vitro pull-down screening. This approach allowed us to identify TET3, a member of the ten-eleven translocation (TET) family proteins, as a partner for TRs....

Hepatocyte Nuclear Factor 4‐Alpha Is Essential for the Active Epigenetic State at Enhancers in Mouse Liver

“…We focused on TET3 because of its high expression in hepatocytes (Fig. A,B) and its known interactions with another nuclear receptor family member, thyroid hormone receptor alpha 1 . Of note, TET3 co‐immunoprecipitation with HNF4A in HepG2 cells, which express high levels of both HNF4A and TET3, confirmed that the two proteins interact (Fig.…”

“…TET2 and TET3 are known to be required for this 5mC oxidation process in hepatocytes . Here, we focused on TET3 because it is more highly expressed compared to other TETs in liver and is known to interact with other TFs . Given that TET2 is also expressed in liver, HNF4A may also interact with TET2 in vivo .…”

Hepatic TET3 contributes to type-2 diabetes by inducing the HNF4α fetal isoform

“…Besides being the key intermediate for TET-mediated DNA demethylation, 5hmC is a potential epigenetic mark; yet, the exact rules that govern how and when TETs proceed beyond 5hmC leading to DNA demethylation are unclear. Recently, non-catalytic functions of TETs have also been described [10][11][12][13] . Mechanistically, TETs as general DNA-binding proteins appear to be recruited to specific gene loci by transcription factors.…”

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…Possible mechanisms of locus-specific 5hmC changes are guided by factors like transcription factors (TF), TET binding proteins, Polycomb Repressive complex 2 (PRC2), histone modifications and post-translational modifications of TFs (Figure 2). TFs like HIF1, thyroid hormone nuclear receptors, retinoic acid receptor (RAR), etc., are shown to interact with TET1 and thus demethylate their target genes by 5hmC [84,[113][114][115]. Apart from TFs, TET-interacting proteins can also recruit it to a particular locus.…”