Side-chain oxysterols suppress the transcription of CTP: Phosphoethanolamine cytidylyltransferase and 3-hydroxy-3-methylglutaryl-CoA reductase by inhibiting the interaction of p300 and NF-Y, and H3K27 acetylation.
CTP: phosphoethanolamine cytidylyltransferase (Pcyt2) is the rate-limiting enzyme in mammalian phosphatidylethanolamine (PE) biosynthesis. Previously, we reported that increasedPcyt2 mRNA levels after serum starvation are suppressed by 25-hydroxycholesterol (HC) (25-HC), and that nuclear factor-Y (NF-Y) is involved in the inhibitory effects. Transcription of Hmgcr, which encodes 3-hydroxy-3-methylglutaryl-CoA reductase, is suppressed in the same manner. However, no typical sterol regulatory element (SRE) was detected in the Pcyt2 promoter. We were therefore interested in the effect of 25-HC on the modification of histones and thus treated cells with histone acetyltransferase inhibitor (anacardic acid) or histone deacetylase inhibitor (trichostatin A). The suppressive effect of 25-HC on Pcyt2 and Hmgcr mRNA transcription was ameliorated by trichostatin A. Anacardic acid, 25-HC and 24(S)-HC suppressed their transcription by inhibiting H3K27 acetylation in their promoters as evaluated by chromatin immunoprecipitation (ChIP) assays. 27-HC, 22(S)-HC and 22(R)-HC also suppressed their transcription, but 7α-HC, 7β-HC, the synthetic LXR agonist T0901317 and cholesterol did not. Furthermore, 25-HC inhibited p300 recruitment to the Pcyt2 and Hmgcr promoters, and suppressed H3K27 acetylation. 25-HC in the medium was easily conducted into cells. Based on these results, we concluded that 25-HC (and other side-chain oxysterols) in the medium was easily transferred into cells, suppressed H3K27 acetylation via p300 recruitment on the NF-Y complex in the Pcyt2 and Hmgcr promoters, and then suppressed transcription of these genes although LXR is not involved.
['Ando|Hiromi|H|', 'Horibata|Yasuhiro|Y|', 'Aoyama|Chieko|C|', 'Shimizu|Hiroaki|H|', 'Shinohara|Yasutake|Y|', 'Yamashita|Satoko|S|', 'Sugimoto|Hiroyuki|H|']
D000107:Acetylation D000818:Animals D023081:CCAAT-Binding Factor D002460:Cell Line D050881:E1A-Associated p300 Protein D006657:Histones D006801:Humans D006888:Hydroxycholesterols D006903:Hydroxymethylglutaryl CoA Reductases D051379:Mice D011401:Promoter Regions, Genetic D012316:RNA Nucleotidyltransferases D014158:Transcription, Genetic
Side-chain oxysterol CTP: phosphoethanolamine cytidylyltransferase p300 NF-Y Pcyt2 25-hydroxycholesterol HMG-CoA reductase Histone acetylation