Journal
MOLECULAR BIOTECHNOLOGY
Volume 63, Issue 1, Pages 53-62Publisher
SPRINGERNATURE
DOI: 10.1007/s12033-020-00283-7
Keywords
SIN3; REST; NRSF; HDAC; Transcriptional repression; Small-molecule inhibitors
Funding
- Lundbeck Foundation's Fellowship program
- Sapere Aude Program of the Danish Council for Independent Research
- Danish Cancer Society
- Carlsberg Foundation
- A.P. Moller Foundation for the Advancement of Medical Sciences
- Fabrikant Einar Willumsens Mindelegat
- Helga og Peter Kornings Fond
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The REST/NRSF-SIN3 transcriptional corepressor complex regulates gene expression through binding to RE1/NRSE sites, with protein complexes including multiple subunits and a druggable histone deacetylase. It is a critical transcriptional repressor complex for biomedical research and potential drug testing.
The repressor element 1 (RE1) silencing transcription factor/neuron-restrictive silencing factor (REST/NRSF) modulates the expression of genes with RE1/neuron-restrictive silencing element (RE1/NRSE) sites by recruiting the switch independent 3 (SIN3) factor and the REST corepressor (COREST) to its N and C-terminal repressor domain, respectively. Both, SIN3 and COREST assemble into protein complexes that are composed of multiple subunits including a druggable histone deacetylase (HDAC) enzyme. The SIN3 core complex comprises the eponymous proteins SIN3A or SIN3B, the catalytically active proteins HDAC1 or HDAC2, the histone chaperone retinoblastoma-associated protein 46/retinoblastoma-binding protein 7 (RBAP46/RBBP7) or RBAP48/RBBP4, the SIN3-associated protein 30 (SAP30), and the suppressor of defective silencing 3 (SDS3). Here, we overcome a bottleneck limiting the molecular characterization of the REST/NRSF-SIN3 transcriptional corepressor complex. To this end, SIN3 genes were amplified from the complementary DNA of neural stem/progenitor cells, and expressed in a baculovirus/insect cell expression system. We show that the isolates bind to DNA harboring RE1/NRSE sites and demonstrate that the histone deacetylase activity is blocked by small-molecule inhibitors. Thus, our isolates open up for future biomedical research on this critical transcriptional repressor complex and are envisioned as tool for drug testing.
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