A Feed-Forward Repression Mechanism Anchors the Sin3/Histone Deacetylase and N-CoR/SMRT Corepressors on Chromatin

Abstract

Transcription in eukaryotes is governed in part by histone acetyltransferase (HAT)- and histone deacetylase (HDAC)-containing complexes that are recruited via activators and repressors, respectively. Here, we show that the Sin3/HDAC and N-CoR/SMRT corepressor complexes repress transcription from histone H3- and/or H4-acetylated nucleosomal templates in vitro. Repression of histone H3-acetylated templates was completely dependent on the histone deacetylase activity of the corepressor complexes, whereas this activity was not required to repress H4-acetylated templates. Following deacetylation, both complexes become stably anchored in a repressor-independent manner to nucleosomal templates containing hypoacetylated histone H3, but not H4, resulting in dominance of repression over activation. The observed stable anchoring of corepressor complexes casts doubt on the view of a dynamic balance between readily exchangeable HAT and HDAC activities regulating transcription and implies that pathways need to be in place to actively remove HDAC complexes from hypoacetylated promoters to switch on silent genes.

We thank Lee Kraus and Gert-Jan Veenstra for advice on in vitro transcriptions and members of the Stunnenberg lab for discussions. We acknowledge Coen Campsteijn for purifying recombinant Xenopus octamers. Furthermore, we thank Mike Carrozza and Jerry Workman for reagents.

The research of M. Vermeulen is supported by The Netherlands Organization for Scientific Research (NWO) and by The Netherlands Proteomics Centre (NPC). Work in the lab of K.L. was supported by NIH grant NIGMS R01GM061909. Work in the lab of R.G.R. was supported by NIH grant DK071900.