Identification and analysis of the promoter region of the human DHCR24 gene: involvement of DNA methylation and histone acetylation

Abstract

Mutations in the DHCR24 gene, which encodes the cholesterol biosynthesis enzyme 3ß-hydroxysterol-∆24 reductase, result in an autosomal recessive disease called desmosterolosis. Further, reduced expression of DHCR24 is found in the temporal cortex of Alzheimer's disease patients. This suggests that variability in the regulatory regions of DHCR24 may contribute to the development of this neurodegenerative disease. In this work, we functionally characterised the proximal fragment of the human DHCR24 gene, for the first time. We show that the transcription of DHCR24 is initiated from a single CpG-rich promoter that is regulated by DNA methylation in some cell types. An activator sequence was also uncovered in the -1203/-665 bp region by reporter gene assays. Furthermore, sodium butyrate (a well-known HDAC inhibitor) increased DHCR24 expression in SH-SY5Y cells by recruiting acetylated core histones H3 and H4 to the enhancer region, as demonstrated by transient transfection and chromatin immunoprecipitation assays. Understanding the regulation of the DHCR24 gene may lead to alternative therapeutic strategies in at least some Alzheimer's patients.

Epigenetic regulation of cholesterol homeostasis

“…They did not report if cholesterol levels were altered by the treatment. Drzewinska et al (2011) reported that 24-dehydrocholseterol reductase ( DHCR24 ), which is not reported in the abovementioned studies, was induced by treatment with either TSA or 5-azacytidine (5AZA) in some, but not all, of the cell types tested. Taken together, the data available in connection with these studies indicates that epigenetic mechanisms are important for the regulation of the cholesterol synthesis pathway.…”

Ultra-high dimensional variable selection with application to normative aging study: DNA methylation and metabolic syndrome

“…Drzewinska et al [30] showed that methylation of the DHCR24 promoter region affects transcriptional efficiency. DNA methylation mediates transcriptional repression via binding of the methylated DNA-binding protein or preserves the binding of transcription factors to their motifs.…”

Histone Acetylation Modifiers in the Pathogenesis of Alzheimer’s Disease

“…In fear-conditioned AD mouse models, the HDAC inhibitors such as trichostatin A (TSA), VPA, SAHA (vorinostat) or sodium butyrate increase the synapse remodeling and enhance the contextual memory by regulating H3/H4 acetylation of relevant gene promoters to enhance hippocampal long-term potentiation (Fischer et al, 2007, 2010; Francis et al, 2009; Guan et al, 2009; Kilgore et al, 2010; Ricobaraza et al, 2012). At the molecular level, sodium butyrate recruits acetylated H3/H4 to the DHCR24 enhancer and increases gene expression which is reduced in the temporal cortex of an AD patient’s brain (Drzewinska et al, 2011). …”