Zodiac (Case 13): Foxp3 — Why is it Potentially Nobel-Prize worthy.

This is the 13th-article of a blog series aiming to introduce Zodiac, a comprehensive tool that reveals genetic interactions in cancer by big-data computation. An introduction of Zodiac is in the 1st article here.

There has been news about a gene called Foxp3, including a prediction from Reuters stating that the gene might be worth a Nobel Prize (see here).

Foxp3 is a transcription factor that potentially regulates many important genes. The main function of Foxp3 is predicted to be regulating the development and function of T cells. It is believed that a subpopulation of T-cells, called regulatory T cells (Tregs),  is specialized in suppressing unnecessary immune function, to avoid auto-immunity (i.e., immune cells attacking the host’s own healthy tissues). When auto-immunity occurs, auto-immune diseases such as inflammatory bowel disease or lupus can occur. Also, in transplantations and immune cancer therapies, avoid auto-immunity is an important and challenging task. Tregs are T-cells that regulate other non-Treg T-cells that execute immune functions.

A few key functions of Foxp3 have been described in the literature, mainly from the landmark paper Sakaguchi et al. 2008, Cell. The first author was invited to give a research lecture at the Nobel Forum in 2013.

  1. Foxp3 is believed to suppress the transcription of IL-2 in Tregs but also activates important surface markers such as IL-2 receptor (CD25), CTLA-4 and GITR. Figure below is taken from Sakaguchi et al. (2008).

template_cell

Zodiac confirms these relationships except the one for GITR. See figure blow. The thick green edges (strong positive associations) between GE’s (gene expression) of Foxp3 and IL-2R/CTLA4 confirm the positive associations found in the Cell paper. Interestingly, there is a green edge between GE of Foxp3 and ME (methylation) of IL2. In other words, there is a positive association of the expression of Foxp3 and methylation of IL2. Therefore, it is likely that when the expression of Foxp3 increases more IL2 will be methylated, potentially leading to the suppression of IL2 transcription. This would agree with the figure above in the Cell paper. As a side note, CTLA4 is the target of one of the earliest FDA-approved cancer immunotherapies, Ipilimumab.

fig1.001

2. Foxp3 is associated with several co-factors, including RUNX1, NFAT, and potentially HDAC and NFKB. See figure below (source: Sakaguchi et al. 2008, Cell).

sakaguchi_3

The plot below  summarizes the relationships among these genes in Zodiac. It appears that Foxp3 is indeed associated with RUNX1 and NFAT, although there is no association between Foxp3 and HDAC or NFKB.

circos1

An important findings in Zodiac is that Foxp3 is associated with a large number of genes with very strong associations. This is reflected in the “beta values” which measures the odds ratio of the associations. For example, there are more than 60 genes associated with Foxp3 in Zodiac with >10 beta values. This means that the odds ratio of the association is over 2^10 = 1024. In addition, these genes appear to possess highly critical cellular functions. A list of these genes are given in the link here –> Gene list.

The top genes are highly enriched with G-protein receptors, such as RXFP4CXCR3CXCL9GNB3CCR7, and GPR132.

Among the gene list, there is a large number of genes related to  T-, B-cells, and immune functions, including the interleukins, CD markers, tumor necrosis factors, and HLA family. The fact that so many important genes are associated with Foxp3 strongly suggests that it plays a critical function in the cellular system.

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