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

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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.

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Acknowledgments

The authors express their gratitude to Dr Lukasz Pulaski for helpful discussions. This work was supported by the Grant No. N N301 164335 from the Polish Ministry of Science and Higher Education, and by the statutory funds of the Institute of Medical Biology and University of Lodz.

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Authors and Affiliations

  1. Department of Molecular Biophysics, University of Lodz, Banacha 12/16, 90-237, Lodz, Poland

    Joanna Drzewinska

  2. Laboratory of Cellular Immunology, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland

    Aurelia Walczak-Drzewiecka

  3. Laboratory of Transcriptional Regulation, Institute of Medical Biology, Polish Academy of Sciences, Lodowa 106, 93-232, Lodz, Poland

    Marcin Ratajewski

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  1. Joanna Drzewinska
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  2. Aurelia Walczak-Drzewiecka
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  3. Marcin Ratajewski
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Correspondence to Marcin Ratajewski.

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Drzewinska, J., Walczak-Drzewiecka, A. & Ratajewski, M. Identification and analysis of the promoter region of the human DHCR24 gene: involvement of DNA methylation and histone acetylation. Mol Biol Rep 38, 1091–1101 (2011). https://doi.org/10.1007/s11033-010-0206-z

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