Identification and analysis of the promoter region of the human DHCR24 gene: involvement of DNA methylation and histone acetylation.
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.
Drzewinska
Joanna
J
Department of Molecular Biophysics, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland.
Walczak-Drzewiecka
Aurelia
A
Ratajewski
Marcin
M
D000107:Acetylation; D000544:Alzheimer Disease / Q000378:metabolism; D002087:Butyrates / Q000378:metabolism; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands; D019175:DNA Methylation; D006367:HeLa Cells; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009419:Nerve Tissue Proteins / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002087:Butyrates; D006657:Histones; D009419:Nerve Tissue Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C499055:DHCR24 protein, human