Effects of a novel, non-toxic histone deacetylase inhibitor on histone acetylation levels in mice
Mentor 1
Karyn Frick
Mentor 2
Sarah Beamish
Start Date
16-4-2021 12:00 AM
Description
The molecular mechanisms that contribute to long-term memory formation remain a point of inquiry for many neuroscientists today. Chromatin remodeling through epigenetic modifications, such as histone acetylation, promotes successful formation of long-term memories by increasing levels gene expression. Research demonstrates that histone deacetylase inhibitors (HDACi) improve memory by preventing the deacetylation of core histone proteins and allowing transcriptional machinery increased access to open chromatin. HDACi are a promising therapeutic target for memory decline, however, the memory enhancing effects of existing HDACi are precluded by their poor toxicity and unwanted solubility. In collaboration with the Chemistry and Biology Departments at UWM, we have developed a novel brain-penetrant HDACi compound, MJM-1, that shows no evidence of toxicity. Data collected from our lab indicates that MJM-1 is capable of enhancing spatial memory in mice. However, it remains unclear the extent to which MJM-1 modifies levels of histone acetylation in the brain. The goal of this work is to determine whether MJM-1 modifies histone acetylation levels in the dorsal hippocampus (DH), a brain region critical for spatial memory formation. Mice received an intraperitoneal injection of negative control (100% DMSO), positive HDACi control sodium butyrate (0.6 g/kg NaBu), or one of three doses of MJM-1 (20, 30, or 40 mg/kg), and the DH was dissected 60 min later. DH tissue was then homogenized so that histones were extracted and posttranslational modifications were kept intact. Here, we demonstrate that i.p. administration of MJM-1 does not increase levels of histone acetylation at one hour. Future steps include assaying DH tissue at shorter timepoints and possibly different brain regions to detect any changes in histone acetylation.
Effects of a novel, non-toxic histone deacetylase inhibitor on histone acetylation levels in mice
The molecular mechanisms that contribute to long-term memory formation remain a point of inquiry for many neuroscientists today. Chromatin remodeling through epigenetic modifications, such as histone acetylation, promotes successful formation of long-term memories by increasing levels gene expression. Research demonstrates that histone deacetylase inhibitors (HDACi) improve memory by preventing the deacetylation of core histone proteins and allowing transcriptional machinery increased access to open chromatin. HDACi are a promising therapeutic target for memory decline, however, the memory enhancing effects of existing HDACi are precluded by their poor toxicity and unwanted solubility. In collaboration with the Chemistry and Biology Departments at UWM, we have developed a novel brain-penetrant HDACi compound, MJM-1, that shows no evidence of toxicity. Data collected from our lab indicates that MJM-1 is capable of enhancing spatial memory in mice. However, it remains unclear the extent to which MJM-1 modifies levels of histone acetylation in the brain. The goal of this work is to determine whether MJM-1 modifies histone acetylation levels in the dorsal hippocampus (DH), a brain region critical for spatial memory formation. Mice received an intraperitoneal injection of negative control (100% DMSO), positive HDACi control sodium butyrate (0.6 g/kg NaBu), or one of three doses of MJM-1 (20, 30, or 40 mg/kg), and the DH was dissected 60 min later. DH tissue was then homogenized so that histones were extracted and posttranslational modifications were kept intact. Here, we demonstrate that i.p. administration of MJM-1 does not increase levels of histone acetylation at one hour. Future steps include assaying DH tissue at shorter timepoints and possibly different brain regions to detect any changes in histone acetylation.
