Stage-Specific Repression by the EKLF Transcriptional Activator

Abstract

Dynamic changes in transcription factor function can be mediated by switching its interaction with coactivators and corepressors. Erythroid Krüppel-like factor (EKLF) is an erythroid cell-specific transcription factor that plays a critical role in β-globin gene activation via its interactions with CBP/p300 and SWI/SNF proteins. Unexpectedly, it also interacts with Sin3A and histone deacetylase 1 (HDAC1) corepressors via its zinc finger domain. We now find that selected point mutants can uncouple activation and repression and that an intact finger structure is not required for interactions with Sin3A/HDAC1 or for transrepression. Most intriguingly, EKLF repression exhibits stage specificity, with reversible EKLF-Sin3A interactions playing a key role in this process. Finally, we have located a key lysine residue that is both a substrate for CBP acetylation and required for Sin3A interaction. These data suggest a model whereby the stage of the erythroid cell alters the acetylation status of EKLF and plays a critical role in directing its coactivator-corepressor interactions and downstream transcriptional effects.

We thank Gordon Keller, Christina Grozinger, and Stuart Schreiber for cells and constructs and the Bieker lab for constructive comments.

This work was supported by NIH grant DK46865 to J.J.B.