UC Berkeley

The exquisite structural and functional complexity of the mammalian body requires the exactingly precise spatial and temporal regulation of gene expression. The most critically regulated step of which is the transcription of DNA to RNA by the elaborate interplay of sequence-specific activators and repressors, chromatin modifiers, coactivators, the basal machinery and RNA polymerase II. Until recently, developmental stage and tissue-specific gene expression patterns were believed to be regulated primarily by the combinatorial actions of DNA binding activators and repressors, while the core machinery was held to be invariant. New evidence suggests that significant differences in coactivator and core promoter recognition complex composition between cell types and developmental time points may facilitate the global changes in gene expression programs necessary to confer functional diversity. Because of its critical role in vertebrate development and homeostasis, the role of coactivator and core promoter recognition complex switching in the developing liver was examined.

This work shows that mouse liver progenitors or hepatoblasts contain significant levels of the canonical core promoter recognition complex TFIID, including the TATA binding protein and multiple associated factors or TAFs, and the canonical coactivator complex Mediator. These complexes and their constitutive proteins are significantly downregulated in adult hepatocytes. Furthermore, the promoters of several TFIID components become enriched for repressive chromatin marks in adult hepatocytes, and an in vitro model of liver development recapitulates the downregulation of these complexes observed in vivo. In contrast, expression of the TBP-related factor TRF3, the TAF7 paralogue TAF7l, and TAF13 is maintained or induced upon hepatic differentiation. Additionally, these proteins associate with high molecular weight complexes in vitro where they are enriched at hepatocyte-specific promoters, and their depletion attenuates hepatic gene induction. Together these observations support a model wherein liver development and the induction of hepatic gene expression requires the down regulation of TFIID and its replacement with one or more complexes likely containing TRF3, TAF7l and TAF13.