The RERE Deacetylase Complex

Histone Deacetylases (HDACs) are important transcriptional regulators which remove acetyl groups from histone tails. Removal of acetyl groups affects gene expression. HDACs are part of large co-regulatory complexes. One of these complexes is called RERE and the core is comprised of: RERE, ATN1 and HDAC1. The RERE protein is a member of the atrophin family and is associated with developmental defects and neurological diseases. The aim of this project was to use structural and biochemical approaches to further our understanding of this poorly characterised complex.

Using peptide binding arrays and fluorescence anisotropy data, the active transcription mark, H3R26me2 was identified as a binding target for the RERE BAH domain. ChIP-sequencing data showed RERE aligned with other active histone marks, which supports the role of RERE as a transcriptional activator. BioID and pulldown approaches suggest RERE forms a complex with SFPQ and NONO. These are co-regulator and splicing factors suggesting that RERE may regulate multiple stages of gene transcription.

Electron microscopy and structural prediction techniques were used to propose a model of the RERE complex. The model shows that RERE does not dimerise through the ELM2 or SANT domains, unlike the homologous MTA1 protein. The RERE zinc finger folds back and interacts with the BAH domain, suggesting that they may work in tandem to interact with a nucleosome. The NONO RRM domains were also shown to form an interaction with the variable region of the BAH domain.

Finally, histone tail peptide inhibitors, Apicidin analogues, and a potent HDAC3 specific inhibitor, were tested against the seven HDAC complexes. HDAC inhibitors are important therapeutic drugs however, they target multiple HDAC complexes which lead to severe side effects. The HDAC complexes exhibited different inhibition profiles against these inhibitors, even with the same HDAC. This suggests that it is possible to target specific HDAC complex.