PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

Fujiki, Katsunori; Shinoda, Akihiro; Kano, Fumi; Sato, Ryuichiro; Shirahige, Katsuhiko; Murata, Masayuki

doi:10.1038/ncomms3262

Cited by 104 publications

(97 citation statements)

References 37 publications

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“…Accordingly, both TET1 and 5hmC often localize to transcriptional start sites (16,17). With regard to nuclear receptors, it was reported previously that peroxisome proliferator-activated receptor-γ has the ability to direct local demethylation around its binding sites via recruitment of TET1 through peroxisome proliferator-activated receptor-γ-induced PARylation (18). In addition, TET3 up-regulation was shown to be responsible for glucocorticoid receptor-induced DNA hypomethylation in neural stem cells (19).…”

Section: Discussionmentioning

confidence: 95%

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

Guan

Guyot

Samarut

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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....

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Section: Discussionmentioning

confidence: 95%

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

Guan

Guyot

Samarut

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[23][24][25][26] Thus, TFs with a TET-dependent demethylation function may comprise a functional subclass. However, because a limited number of TFs have been identified in this subclass, it is unclear how major this subclass is.…”

Section: Discussionmentioning

confidence: 99%

“…22 Recently, several TFs, which play important roles in cellular differentiations, were reported to induce DNA demethylation by interacting with TET proteins. [23][24][25][26] However, it has not been elucidated whether RUNX1 also contributes to regulating DNA methylation. Here, we demonstrate that RUNX1 contributes site-directed DNA demethylation by recruitment of DNA demethylation enzymes.…”

Section: Introductionmentioning

confidence: 99%

RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells

et al. 2017

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“…adiponectin and adiponectin receptor 2, that are targeted by PPARγ, showed differential methylation within their PPARγ DNA binding sites at later stages of adipogenesis (Takada et al, 2014). PPARγ has been shown to induce local DNA demethylation at its binding sites via poly(ADP-ribosyl)ation of the transcription factor/coactivator complex and subsequent recruitment of Tet proteins that oxidize 5-methylcytosine (5-mC) to 5-hydroxymethylcytosine, resulting in the replacement of 5-mC by cytosine (Fujiki et al, 2013). It can be concluded that the DNA methylome of mature adipocytes develops early in the lineage differentiation, and that the large majority of adipocyte genes is 'ready' for transcriptional induction as early as the preadipocyte stage.…”

Section: Adipogenesismentioning

confidence: 99%

The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction

Castro

Grune

Speckmann

2016

Biological Chemistry

125

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White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.

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PPARγ-induced PARylation promotes local DNA demethylation by production of 5-hydroxymethylcytosine

Cited by 104 publications

References 37 publications

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

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

RUNX1 regulates site specificity of DNA demethylation by recruitment of DNA demethylation machineries in hematopoietic cells

The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction

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