RT Journal Article
SR Electronic
T1 NRSF–mediated repression of neuronal genes in developing brain persists in the absence of NRSF-Sin3 interaction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 245993
DO 10.1101/245993
A1 Alicia M. Hall
A1 Annabel K. Short
A1 Akanksha Singh-Taylor
A1 Jennifer Daglian
A1 Tadashi Mishina
A1 William K. Schmidt
A1 Hiroyuki Kouji
A1 Tallie Z. Baram
YR 2018
UL http://biorxiv.org/content/early/2018/01/23/245993.abstract
AB Repression of target genes by the transcriptional repressor neuronal restrictive silencing factor (NRSF)/repressor element 1 silencing transcription factor (REST) contributes to enduring plasticity in the developing brain. However, the cofactor(s) interacting with NRSF to enable target gene repressor are not well understood, and may vary among neuronal populations and brain regions as well as with different contexts. Here we employed the novel designer drug mS-11 to block the interactions of the cofactor Sin3 with NRSF. We tested if NRSF-Sin3 interaction is required for repression of NRSF target genes in developing hypothalamus after activity-dependent modulation of NRSF function. In the hypothalamus in vitro, blocking glutamatergic neurotransmission robustly increased NRSF binding to the target gene Crh, resulting in its repression. Blocking the binding of NRSF to the chromatin with decoy NRSE-oligodeoxynucleotides abrogated this repression. In contrast, mS-11 at several concentrations did not impede Crh repression. NRSF-mediated repression may underlie disease processes such as the onset of epilepsy. Therefore, identifying small-molecule antagonists of NRSF is crucial for the development of disease-preventing or modifying interventions.