chapter  8
Transcriptional Profiling of the Hepatic Growth Response
Pages 8

Coordinated changes in gene regulatory networks involved in growth or homeostatic functions are essential for restoration of liver mass and survival during the post-hepatectomy period. Cluster analysis has been used in the majority of published array studies to identify global changes in biological functions that occur in the regenerating liver.12' 15,17 This ap­ proach has demonstrated an overall trend towards increased expression of genes involved in protein synthesis and a reduction in most aspects of intermediary metabolism.13,14 Our labo­ ratory has utilized the recently developed Expression Analysis Systematic Explorer (EASE) program to identify additional biologically relevant themes important for homeostatic and proliferative responses in the regenerating liver during multiple phases of the cell cycle.18 Using the EASE program, we identified a shift in the transcriptional program from genes involved in lipid and hormone biosynthesis in the quiescent liver to those contributing to cytoskeleton assembly and DNA synthesis during the posthepatectomy period (Fig. I ) .16 The results of EASE analysis emphasize the importance of coordinated shifts in transcrip­ tional sub-programs that control discrete biological programs in the regenerating liver. The mechanisms responsible for synchronized transcription of genes in the partial hepatectomy model have not been investigated because the genetic analysis of the contribution of tran­ scription factors has been confined to individual regulatory proteins and a small set of indi­ vidual target genes. The importance of coactivator proteins in other mammalian systems for integration of transcriptional responses to physiologic signals suggests that coactivators and perhaps corepressors may be involved in coordinating transcription of genes that together regulate complex biological processes in the regenerating liver (ref. 19 and references therein). Identification of promoters bound by specific coactivator proteins using arrays containing promoter sequences (see below: Location analysis) promises to provide new insights regard­ ing the contribution of coactivators for coordinating transcriptional programs responsible for either growth or metabolic processes in this system in the future. However, this approach w ill require the development of new experimental and computational tools, because coactivators and corepressors do not contact DNA directly and therefore do not converge on a single consensus binding site.