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Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.

ABSTRACT: The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-? (TGF-?)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-?-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer I). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dominant site in enhancer I and a subordinate site in the promoter. This led to increased histone acetylation in the region of the Smad3 binding site and increased binding of pSmad3. Cytokine (IL-27) inhibition involved binding of pStat3 to a gene silencer in a second conserved enhancer region (enhancer II) downstream from enhancer I; this led to loss of pSmad3 binding to enhancer I. Thus, control of accessibility and binding of pSmad3 provides a common framework for positive and negative regulation of TGF-?-induced Foxp3 transcription.

SUBMITTER: Xu L

PROVIDER: S-EPMC2972198 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.

Xu Lili L Kitani Atsushi A Stuelten Christina C McGrady George G Fuss Ivan I Strober Warren W

Immunity 20100901 3

The molecular mechanisms underlying retinoic acid (RA) augmentation of T cell receptor (TCR) and transforming growth factor-β (TGF-β)-induced Foxp3 transcription and inhibition of the latter by cytokines such as IL-27 were here shown to be related processes involving modifications of baseline (TGF-β-induced) phosphorylated Smad3 (pSmad3) binding to a conserved enhancer region (enhancer I). RA augmentation involved the binding of retinoic acid receptor (RAR) and retinoid X receptor (RXR) to a dom ...[more]

PMID: 20870174

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Project description:Growth factors, such as myostatin (Mstn), play an important role in regulating post-natal myogenesis. In fact, loss of Mstn has been shown to result in increased post-natal muscle growth through enhanced satellite cell functionality; while elevated levels of Mstn result in dramatic skeletal muscle wasting through a mechanism involving reduced protein synthesis and increased ubiquitin-mediated protein degradation. Here we show that miR-27a/b plays an important role in feed back auto-regulation of Mstn and thus regulation of post-natal myogenesis. Sequence analysis of Mstn 3' UTR showed a single highly conserved miR-27a/b binding site and increased expression of miR-27a/b was correlated with decreased expression of Mstn and vice versa both in vitro and in mice in vivo. Moreover, we also show that Mstn gene expression was regulated by miR-27a/b. Treatment with miR-27a/b-specific AntagomiRs resulted in increased Mstn expression, reduced myoblast proliferation, impaired satellite cell activation and induction of skeletal muscle atrophy that was rescued upon either blockade of, or complete absence of, Mstn. Consistent with this, miR-27a over expression resulted in reduced Mstn expression, skeletal muscle hypertrophy and an increase in the number of activated satellite cells, all features consistent with impaired Mstn function. Loss of Smad3 was associated with increased levels of Mstn, concomitant with decreased miR-27a/b expression, which is consistent with impaired satellite cell function and muscular atrophy previously reported in Smad3-null mice. Interestingly, treatment with Mstn resulted in increased miR-27a/b expression, which was shown to be dependent on the activity of Smad3. These data highlight a novel auto-regulatory mechanism in which Mstn, via Smad3 signaling, regulates miR-27a/b and in turn its own expression. In support, Mstn-mediated inhibition of Mstn 3' UTR reporter activity was reversed upon miR-27a/b-specific AntagomiR transfection. Therefore, miR-27a/b, through negatively regulating Mstn, plays a role in promoting satellite cell activation, myoblast proliferation and preventing muscle wasting.

Dataset Information

Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.

Publications

Positive and negative transcriptional regulation of the Foxp3 gene is mediated by access and binding of the Smad3 protein to enhancer I.

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