Search

Prader-Willi syndrome (PWS) is a complex and multisystem neurobehavioral disorder. The molecular mechanism of PWS is deficiency of paternally expressed gene gene or genes from the chromosome 15q11-q13. Due to imprinted gene regulation, the same genes in the maternal chromosome 15q11-q13 are structurally intact but transcriptionally repressed by an epigenetic mechanism. The unique molecular defect underlying PWS renders an exciting opportunity to explore epigenetic-based therapy to reactivate the expression of repressed PWS genes from the maternal chromosome. Inactivation of H3K9m3 methyltransferase SETDB1 and zinc finger protein ZNF274 results in reactivation of SNRPN and SNORD116 cluster from the maternal chromosomes in PWS patient iPSCs and iPSC-derived neurons, respectively. High content screening of small molecule libraries using cells derived from transgenic mice carrying the SNRPN-EGFP fusion protein has discovered that inhibitors of EHMT2/G9a, a histone 3 lysine 9 methyltransferase, are capable of reactivating expression of paternally expressed SNRPN and SNORD116 from the maternal chromosome, both in cultured PWS patient-derived fibroblasts and in a PWS mouse model. Treatment with an EMHT2/G9a inhibitor also rescues perinatal lethality and failure to thrive phenotypes in a PWS mouse model. These findings present the first evidence to support a proof-of-principle for epigenetic-based therapy for the PWS in humans., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oleanolic acid (OA) has neurotrophic effects on neurons, although its use as a neurological drug requires further research. In the present study, we investigated the effects of OA and OA derivatives on the neuronal differentiation of rat hippocampal neural progenitor cells. In addition, we investigated whether the class II histone deacetylase (HDAC) 5 mediates the gene expression induced by OA. We found that OA and OA derivatives induced the formation of neurite spines and the expression of synapse-related molecules. OA and OA derivatives stimulated HDAC5 phosphorylation, and concurrently the nuclear export of HDCA5 and the expression of HDAC5 target genes, indicating that OA and OA derivatives induce neural differentiation and synapse formation via a pathway that involves HDAC5 phosphorylation.

Both erythropoietin (EPO) and carbamylated EPO (cEPO) have been shown to increase the length of neurites and spine density in neurons. However, the molecular mechanism underlying the EPO- and cEPO-induced neuronal differentiation has yet to be investigated. To address this issue, we investigated epigenetic modifications that regulate gene expression in neurons. Neurons treated with EPO or cEPO display an upregulation of E1A-binding protein (p300) and p300-mediated p53 acetylation, possibly increasing the transactivation activity of p53 on growth-associated protein 43 (GAP43). Treatment of cells with cEPO markedly increases spine formation and potentiates p300-mediated transactivation of PSD95, Shank2 and 3 compared to EPO. These results demonstrate that cEPO controls neuronal differentiation via acetylation of transcription factors and subsequent transactivation of target genes. These findings have important medical implications because cEPO is of interest in the development of therapeutic agents against neuropsychiatric disorders., (Copyright © 2014 Elsevier Inc. All rights reserved.)