Reconstructing Gene Cooperation Network of Lipotoxicity by Synergy Analysis

Reconstructing Gene Cooperation Network of Lipotoxicity by Synergy Analysis

Xuewei Wang¹, Aritro Nath⁴, Xuerui Yang¹, Amanda Portis¹, S. Patrick Walton¹, Christina Chan^1-5

¹Department of Chemical Engineering and Material Science, Michigan State University, East Lansing, MI 48824, USA; ²Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, USA; ³Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA; ⁴Genetics program, Michigan State University, East Lansing, MI 48824, USA; ⁵Center for Systems Biology, Michigan State University, East Lansing, MI 48824

Co-operation between multiple genes plays an important role in regulating complex cellular activities and the ensuing phenotypes that are observed. As proof-of-concept we present an integrative strategy to construct a phenotype-specific gene cooperation network of lipotoxicity induced by saturated free fatty acids (FFAs), which have been implicated in a diverse number of diseases. Given that saturated FFAs can modulate multiple intracellular metabolic pathways involved in the induction of lipotoxicity, we first select a subset of relevant genes by integrating the gene expression and metabolite profiles. This strategy reflects, in part, the "multi-level" regulatory characteristic of cellular activities. With a subset of genes selected, we then adopt an information-theoretic concept of synergy to quantify the cooperative effects of genes on lipotoxicity and construct a cooperative gene network (synergy network).

Subsequent analyses confirmed that the method indeed captured gene pairs that provided synergistic information on the phenotypes, i.e. the identified pairs of genes discriminated the phenotype better than either alone. From the network analysis we identify that desmoplakins (DSP) plays an important role in lipotoxicity. DSP are obligatory components of desmosomes at intercellular junctions and are necessary for desmosomal adhesion. Together with plakoglobin, DSP forms an anchor for intermediate filament attachment at the desmosomal plaque. Figure 1 shows the effect of palmitate on cellular expression of DSP. The cells treated with palmitate show a significant decrease in DSP expression as compared to untreated control cells. On the other hand, cells grown on insulin containing medium subsequent to palmitate treatment restored some of the DSP expression. Treatment with palmitate has been shown to affect cellular adherence and cytoskeletal structure in hepatocytes, although the exact mechanism and whether DSP is involved in mediating these processes was not known (Swagell et al, 2005). This opens a possible mechanism by which palmitate could lead to the development and progression of liver disease, i.e. non-alcholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). Indeed, studies have suggested that the loss of desmosomes may be associated with epithelial to mesenchymal transition (EMT) -- a means by which cells may acquire malignant characteristics (Chidgey and Dawson, 2007).

Figure1 cellular expression of DSP in three conditions, including control, palmitate, and palmitate plus insulin

In contrast to synergy analysis, a network reconstructed from differential correlation was unable to identify DSP as a being important to lipotoxicity. In summary, our analysis recovered known mechanisms, as well as revealed novel target genes involved in the induction of lipotoxicity for further investigation.

References

Swagell, C., Henly, D., Morris, C.P. Expression analysis of a human hepatic cell line in response to palmitate. Biochem. Biophys. Res. Commun. (2005) 328, 432-441.

Chidgey, M., Dawson, C. Desmosomes: a role in cancer? British Journal of Cancer (2007) 96, 1783-1787.