FOXP3: genetic and epigenetic implications for autoimmunity

Abstract

FOXP3 plays an essential role in the maintenance of self-tolerance and, thus, in preventing autoimmune diseases. Inactivating mutations of FOXP3 cause immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. FOXP3-expressing regulatory T cells attenuate autoimmunity as well as immunity against cancer and infection. More recent studies demonstrated that FOXP3 is an epithelial cell-intrinsic tumor suppressor for breast, prostate, ovary and other cancers. Corresponding to its broad function, FOXP3 regulates a broad spectrum of target genes. While it is now well established that FOXP3 binds to and regulates thousands of target genes in mouse and human genomes, the fundamental mechanisms of its broad impact on gene expression remain to be established. FOXP3 is known to both activate and repress target genes by epigenetically regulating histone modifications of target promoters. In this review, we first focus on germline mutations found in the FOXP3 gene among IPEX patients, then outline possible molecular mechanisms by which FOXP3 epigenetically regulates its targets. Finally, we discuss clinical implications of the function of FOXP3 as an epigenetic modifier. Accumulating results reveal an intriguing functional convergence between FOXP3 and inhibitors of histone deacetylases. The essential epigenetic function of FOXP3 provides a foundation for experimental therapies against autoimmune diseases.

Figure. 1

A pull-push model for FOXP3-mediated gene regulation. According to this model, FOXP3 recruits MOF to its binding sites, resulting in H4K16 acetylation (H4K16ac) of target genes. The consequences of this modification can be determined by subsequent tri-methylation (me3) at either H3K4 or H3K27. Gene activation can be achieved if H4K16ac is complemented by H3K4me3. This might be achieved by displacements of histone trimethyl-de-methylase, such as PLU-1, from its binding sites. This H4K16ac/H3K4me3 histone code will be recognized by Bromo- and PhD-domain containing BPTF which recruits Nurf complex to the loci. On the other hand, we speculate that the potentially active H4K16ac can be overridden by H3K27me3. The latter may possibly be achieved by either recruitments of EZH2 or displacements of H3K27me demethylase KDM6A or KDM6B. The repressive H3K27 code will be recognized by PRC1 which in turn recruits HDAC for gene repression.

Figure. 2

Functional convergence between FOXP3 and HDAC inhibitors (HDACi). 1: FOXP3 promotes histone acetylation by either recruiting MOF to, or displacing HDACs from, FOXP3 target genes, while HDACi achieves the same goal by reducing histone deacetylation. 2: FOXP3 and HDACi both inhibit HDAC activity. 3: Since FOXP3 activity is regulated by its acetylation by TIP60, a general HDACi may have a similar effect on FOXP3 activity.