Message in a nucleus: signaling to the transcriptional machinery

Abstract

Tissue differentiation and signal transduction involve dramatic changes in gene expression. These changes can be brought about by the expression or activation of sequence-specific transcription factors. In order to regulate their target genes, such factors must navigate the intricate chromatin environment and engage the complex basal transcriptional machinery. We discuss three mechanisms through which signaling pathways can interact with complexes that alter chromatin structure or recruit RNA polymerase II. Signals that promote differentiation may alter the properties of such transcriptional regulatory complexes by incorporating tissue-specific subunits. Alternatively, adaptor subunits specialized to interact with specific transcription factors may allow a single complex to respond to multiple signals. Finally, individual regulatory proteins may integrate a variety of signals, allowing crosstalk between pathways.

Figure 1. Mechanisms for interaction between signaling pathways and the general transcriptional machinery

(A) Developmental signals that trigger differentiation can result in the replacement of a core transcriptional complex. When myoblasts differentiate into myotubes, TFIID is replaced by a smaller complex containing TAF3 and the TBP homologue TRF3. This complex recognizes the promoters of muscle-specific genes. (B) Transcriptional complexes can contain subunits specialized to act as adaptors for signal-regulated transcription factors. The Mediator complex interacts with pol II and GTFs through its head module (turquoise), and with multiple DNA-binding proteins and coactivators through individual adaptor subunits in its middle (blue), tail (purple) and kinase (gray) modules. Only transcription factors regulated by signaling pathways are shown; they are represented on a single enhancer region for convenience, but would in fact recruit the complex to different target genes. (C) Some transcriptional regulators can integrate multiple inputs, allowing crosstalk between signaling pathways. The histone acetyltransferase CBP is recruited (black arrows) by a large number of signal-regulated and other transcription factors, again represented on a single hypothetical enhancer. Some of these factors are themselves acetylated by CBP (green arrows). The activity and binding preferences of CBP itself can also be regulated by post-translational modifications controlled by signaling pathways.