Differences in hepatic transcriptional regulatory networks due to body condition score at calving in grazing dairy cattle
Despite recent progress in nutrigenomics of peripartal dairy cattle, many components of transcriptional regulation in hepatic networks remain unknown. The objective of this study was to use gene network analysis on hepatic microarray data to identify transcription regulators (TR) and their target genes. Holstein-Friesian cows managed to achieve a high (H, 5.5 BCS), medium (M, 4.5 BCS), or low (L, 3.5 BCS) BCS (10-point scale) were used. Target BCS at calving were achieved by managing feed allowance before dry off. Post-calving, cows were allocated pasture and pasture silage (predominantly perennial ryegrass). Liver from 10 cows per BCS group was biopsied on wk 1, 3, and 5 postpartum. A whole-transcriptome bovine microarray (Agilent) was used. An ANOVA with repeated measures using PROC MIXED resulted in 5,888 differentially-expressed genes (DEG) due to main effect of BCS (False Discovery Rate <0.05) and 327 differentially expressed genes due to BCS × wk. TF network analysis was performed with Ingenuity Pathway Analysis (IPA). The network analysis uncovered TP53 as a central hub regulating a large spectrum of genes altered by BCS. Expression of TP53 was overall greater in H vs. M and L vs. M, but lower in H vs L. Other important TR altered by BCS were CTNNB1, SREBF1, RXRA, STAT1, NFKBIA and YWHAH. Among DEG with a BCS × wk effect due to H vs. M or L vs. M on wk 1, HNF4A was among 10 TR uncovered to have the greatest number of targets. Unlike wk 1, out of 9 TR identified in wk 3, the expression of MYC was downregulated in H vs. L but this TR had the greatest number of targets. Similarly, MYC had the greatest number of targets in L vs. M on wk 3 but was upregulated. Contrary to wk 1, on wk 5 the expression of MYC was upregulated in H vs. L and FOXP3 was identified as an important TR. Expression of FOXP3 on wk 5 was downregulated in H vs. M but among 16 TR identified it had the greatest number of targets. It is noteworthy that TP53, MYC, and FOXP3 are key controllers of cell proliferation/apoptosis in non-ruminant tissues/cells. Although HNF4A also is related with liver development, it has broader functions in terms of controlling expression of metabolic genes. Preliminary interpretation suggests an important role of a few TR in the control of liver function.
Keywords: gene networks, bioinformatics, systems biology