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

Hiromi Ando; Yasuhiro Horibata; Chieko Aoyama; Hiroaki Shimizu; Yasutake Shinohara; Satoko Yamashita; Hiroyuki Sugimoto

doi:10.1016/j.jsbmb.2019.105482

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

J Steroid Biochem Mol Biol. 2019 Dec:195:105482. doi: 10.1016/j.jsbmb.2019.105482. Epub 2019 Sep 30.

Authors

Hiromi Ando¹, Yasuhiro Horibata¹, Chieko Aoyama¹, Hiroaki Shimizu¹, Yasutake Shinohara¹, Satoko Yamashita¹, Hiroyuki Sugimoto²

Affiliations

¹ Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu 321-0293, Japan.
² Department of Biochemistry, Dokkyo Medical University School of Medicine, Mibu 321-0293, Japan. Electronic address: h-sugi@dokkyomed.ac.jp.

PMID: 31580889
DOI: 10.1016/j.jsbmb.2019.105482

Abstract

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.

Keywords: 25-hydroxycholesterol; CTP: phosphoethanolamine cytidylyltransferase; HMG-CoA reductase; Histone acetylation; NF-Y; Pcyt2; Side-chain oxysterol; p300.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylation / drug effects
Animals
CCAAT-Binding Factor / metabolism*
Cell Line
E1A-Associated p300 Protein / metabolism*
Histones / metabolism*
Humans
Hydroxycholesterols / pharmacology*
Hydroxymethylglutaryl CoA Reductases / genetics*
Mice
Promoter Regions, Genetic
RNA Nucleotidyltransferases / genetics*
Transcription, Genetic / drug effects

Substances

CCAAT-Binding Factor
Histones
Hydroxycholesterols
nuclear factor Y
25-hydroxycholesterol
HMGCR protein, human
Hydroxymethylglutaryl CoA Reductases
E1A-Associated p300 Protein
EP300 protein, human
RNA Nucleotidyltransferases
Ethanolamine-phosphate cytidylyltransferase