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Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line
School of Medicine, Institute of Biomedicine, University of Eastern Finland, POB 1627, Kuopio FI-70211, Finland
Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
* Author to whom correspondence should be addressed.
Received: 28 August 2013; in revised form: 19 September 2013 / Accepted: 26 September 2013 / Published: 16 October 2013
Abstract: Genome- and transcriptome-wide data has significantly increased the amount of available information about primary 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) target genes in cancer cell models, such as human THP-1 myelomonocytic leukemia cells. In this study, we investigated the genes G0S2, CDKN1A and MYC as master examples of primary vitamin D receptor (VDR) targets being involved in the control of cellular proliferation. The chromosomal domains of G0S2 and CDKN1A are 140–170 kb in size and contain one and three VDR binding sites, respectively. This is rather compact compared to the MYC locus that is 15 times larger and accommodates four VDR binding sites. All eight VDR binding sites were studied by chromatin immunoprecipitation in THP-1 cells. Interestingly, the site closest to the transcription start site of the down-regulated MYC gene showed 1,25(OH)2D3-dependent reduction of VDR binding and is not associated with open chromatin. Four of the other seven VDR binding regions contain a typical DR3-type VDR binding sequence, three of which are also occupied with VDR in macrophage-like cells. In conclusion, the three examples suggest that each VDR target gene has an individual regulatory scenario. However, some general components of these scenarios may be useful for the development of new therapy regimens.
Keywords: vitamin D receptor; vitamin D; G0S2; CDKN1A; MYC; genomics; chromatin; gene regulation
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Ryynänen, J.; Seuter, S.; Campbell, M.J.; Carlberg, C. Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line. Cancers 2013, 5, 1221-1241.
Ryynänen J, Seuter S, Campbell MJ, Carlberg C. Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line. Cancers. 2013; 5(4):1221-1241.
Ryynänen, Jussi; Seuter, Sabine; Campbell, Moray J.; Carlberg, Carsten. 2013. "Gene Regulatory Scenarios of Primary 1,25-Dihydroxyvitamin D3 Target Genes in a Human Myeloid Leukemia Cell Line." Cancers 5, no. 4: 1221-1241.