Pathways analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line

Authors: Li, Congjun - Cj; Li, Robert; WANG, YONG-HONG - SAIC-FREDERICK-NCI; Elsasser, Theodore

Submitted to: Functional and Integrative Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/14/2006
Publication Date: 11/14/2006
Citation: Li, C.J., Li, R.W., Wang, Y.H. Elsasser, T.H. 2007. Pathway analysis identifies perturbation of genetic networks induced by butyrate in a bovine kidney epithelial cell line. Functional and Integrative Genomics. 7:193-205.

Interpretive Summary: Ruminant species use the short-chain volatile fatty acids (VFA), acetate, propionate, and butyrate for up to 70% of their nutrient energy requirements. The inherent VFA dependence of ruminant cells was exploited in order to add a level of increased sensitivity to the study of the role of butyrate gene response elements in regulatory biochemical pathways. Global gene expression profiles of the bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR) = 0 % were identified. The majority of these genes regulated by butyrate were associated with cell cycle progression and cell death regulation. A large number of these differentially expressed genes were newly identified and their relationship to butyrate had not been reported before. The detailed mechanisms by which butyrate induces cell growth arrest and apoptosis were analyzed using the Ingenuity Pathways Knowledge Base. The functional category and pathway analyses of the microarray data revealed that four canonical pathways (Cell cycle: G2/M DNA damage checkpoint; pyrimidine metabolism; Cell cycle: G1/S Checkpoint Regulation; and purine metabolism) were significantly perturbed. The biologically relevant networks and pathways of these genes were also identified. IGF2, TGFB1, TP53, E2F4 and CDC2 were established as being centered in these genomic networks. The present findings provide a basis for understanding the full range of the biological roles and the molecular mechanisms that butyrate may play in animal cell growth, proliferation, and energy metabolisms.

Technical Abstract: Ruminant species have evolved to metabolize the short-chain volatile fatty acids (VFA), acetate, propionate, and butyrate to fulfill up to 70% of their nutrient energy requirements. The inherent VFA dependence of ruminant cells was exploited in order to add a level of increased sensitivity to the study of the role of butyrate gene response elements in regulatory biochemical pathways. Global gene expression profiles of the bovine kidney epithelial cells regulated by sodium butyrate were investigated with high-density oligonucleotide microarrays. 450 genes significantly regulated by butyrate with a median False Discovery Rate (FDR) = 0 % were identified. The majority of these genes regulated by butyrate were associated with cell cycle progression and cell death regulation. A large number of these differentially expressed genes were newly identified and their relationship to butyrate had not been reported before. The detailed mechanisms by which butyrate induces cell growth arrest and apoptosis were analyzed using the Ingenuity Pathways Knowledge Base. The functional category and pathway analyses of the microarray data revealed that four canonical pathways (Cell cycle: G2/M DNA damage checkpoint; pyrimidine metabolism; Cell cycle: G1/S Checkpoint Regulation; and purine metabolism) were significantly perturbed. The biologically relevant networks and pathways of these genes were also identified. IGF2, TGFB1, TP53, E2F4 and CDC2 were established as being centered in these genomic networks. The present findings provide a basis for understanding the full range of the biological roles and the molecular mechanisms that butyrate may play in animal cell growth, proliferation, and energy metabolisms.