HDAC inhibition imparts beneficial transgenerational effects in Huntington's disease mice via altered DNA and histone methylation

摘要: Increasing evidence has demonstrated that epigenetic factors can profoundly influence gene expression and, in turn, resistance or susceptibility to disease. Epigenetic drugs, such as histone deacetylase (HDAC) inhibitors, are finding their way into clinical practice, although exact mechanisms of action unclear. To identify associated with HDAC inhibition, we performed microarray analysis on brain and muscle samples treated the HDAC1/3-targeting inhibitor, HDACi 4b. Pathways analyses datasets implicate DNA methylation significantly inhibition. Further assessment changes elicited by 4b human fibroblasts from normal controls patients Huntington's disease (HD) using Infinium HumanMethylation450 BeadChip revealed a limited, but overlapping, subset methylated CpG sites were altered inhibition both HD cells. Among loci Y chromosome-linked genes, KDM5D, which encodes Lys (K)-specific demethylase 5D, showed increased at several cells, well isolated sperm drug-treated male mice. Further, demonstrate first filial generation (F1) offspring transgenic mice show improved phenotypes compared F1 vehicle-treated mice, association Kdm5d expression, decreased H3 Lys4 (K4) (H3K4) CNS offspring. Additionally, overexpression mutant striatal cells improves metabolic deficits. These findings indicate inhibitors elicit transgenerational effects, via cross-talk between different mechanisms, have an impact beneficial manner.