Chromatin: receiver and quarterback for cellular signals

Abstract

Signal transduction pathways converge upon sequence-specific DNA binding factors to reprogram gene expression. Transcription factors, in turn, team up with chromatin modifying activities. However, chromatin is not simply an endpoint for signaling pathways. Histone modifications relay signals to other proteins to trigger more immediate responses than can be achieved through altered gene transcription, which might be especially important to time-urgent processes such as the execution of cell-cycle check points, chromosome segregation, or exit from mitosis. In addition, histone-modifying enzymes often have multiple nonhistone substrates, and coordination of activity toward different targets might direct signals both to and from chromatin.

Figure 1. Regulation of RelA/NF-κB by a phospho-methyl switch and in response to DNA damage

A) Methylation of RelA K310 by SETD6 creates a binding site for GLP, which in turn methylates H3K9 at NF-κB target genes to inhibit transcription. Phosphorylation of RelA at S311 by PKCζ blocks binding of GLP to RelA (Levy et al., 2011) and, along with other RelA modifications not shown, promotes its interaction with CBP, leading to histone acetylation and activation of NF-κB target genes (Duran et al., 2003). B) Phosphorylation of NEMO by ATM in response to a DSB promotes its export from the nucleus. In the cytoplasm, NEMO activates the IKK complex, leading to IκB phosphorylation and degradation and NF-κB (RelA-p50) translocation to the nucleus where it can activate transcription as shown in (A). Note that some ATM may translocate with NEMO to the cytoplasm and participate in IKK activation.

Figure 2. H2Bub passes signals to different receivers to regulate different cellular processes dependent on its chromosomal location

In yeast, Bre1-mediated ubiquitylation of H2B promotes H3K4 and Dam1 methylation by Set1 and H3K79 methylation by Dot1. Depending on its location, H2Bub can participate in the regulation of transcription, chromosome segregation, cell cycle checkpoints, and mitotic exit.