SUMO Promotes HDAC-Mediated Transcriptional Repression

Abstract

Recently, SUMO modification has been shown to impart repressive properties on several transcriptional regulatory proteins. Indeed, the ETS domain transcription factor Elk-1 is modified by SUMO, and this modification is reversed by ERK MAP kinase pathway activation. This causes a switch from a repressive to activated state. However, the mechanism(s) of SUMO-mediated transcriptional repression is unclear. Here, we have investigated how sumoylation of Elk-1 leads to transcriptional repression. We demonstrate that sumoylation of Elk-1 results in the recruitment of histone deacetylase activity to promoters. In particular, our data point to a key role for HDAC-2. This recruitment leads to decreased histone acetylation and hence transcriptional repression at Elk-1 target genes. Thus, our data demonstrate an important integration point for two protein-modifying pathways in the cell, the SUMO and deacetylation pathways, that combine to promote transcriptional repression.

SUMOylation of the Corepressor N-CoR Modulates Its Capacity to Repress Transcription

“…SUMO modification has been described to influence the assembly of transcription factors on promoters and the recruitment of chromatin-modifying enzymes. SUMOylation of Elk-1, for example, results in the recruitment of histone deacetylase activity, in particular HDAC-2, to promoters (Yang and Sharrocks, 2004). The N-terminal portion of NCoR interacts with HDAC3 and Sin3A (Heinzel et al, 1997;Guenther et al, 2000;Wen et al, 2000).…”

“…SUMOylation of N-CoR RDI or RDIII may thus very well play important roles in regulating the interaction with nuclear receptors. Several reports showed that class I (HDAC1, HDAC2) and class II HDACs (HDAC4, HDAC6) are targets for SUMO modification (David et al, 2002;Kirsh et al, 2002;Girdwood et al, 2003;Yang and Sharrocks, 2004). Interestingly, histones are also subject to SUMOylation and posttranslational modifications play important roles in the regulation of chromatin structure and function.…”

“…Protein Inhibitors of Activated Stat (PIAS; Johnson and Gupta, 2001;Schmidt and Muller, 2003), RanBP2 (Pichler et al, 2002), and Polycomb group protein Pc2 have been shown to act as SUMO E3 ligases (Kagey et al, 2003). SUMO modification of transcription factors is often associated with transcriptional repression (Gill, 2004;Hay, 2005) and SUMO negatively affects the transcriptional activating function of transcription factors, such as Elk-1 or nuclear hormone receptors (Abdel-Hafiz et al, 2002;Sapetschnig et al, 2002;Girdwood et al, 2003;Yang and Sharrocks, 2004). However, the molecular basis of how SUMO represses transcription factor function is not well understood.…”

MAP kinases as structural adaptors and enzymatic activators in transcription complexes

“…However, indirect routes by which MAPK cascades can cause localized nucleosomal modification at inducible genes -for example, by promoting association of histone acetyltransferases (HATs) with transcription factors in a phosphorylation-dependent manner (Mayr and Montminy, 2001;Yang et al, 2003) -have also emerged, linking localized histone acetylation with MAPK activation. A recently reported variation of this involves the interplay between MAPKregulated SUMOylation of the transcription factor Elk1 and its interaction with histone deacetylases (Yang and Sharrocks, 2004). Finally, recent evidence from yeast indicates a novel role for MAPKs as components of promoter-bound transcription complexes.…”

Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

“…Histone deacetylases (HDACs) are generally correlated with repression of transcription and can be recruited to sumoylated transcription factor complexes. For example, SUMO modification of the transcription factor Elk-1 has been correlated with increased association with HDAC2 [31]. Additionally, sumoylation of the co-activator p300 is associated with increased levels of HDAC6 [32].…”