title: CpG signalling, H2A.Z/H3 acetylation and microRNA-mediated deferred self-attenuation orchestrate foetal NOS3 expression.
abstract: BACKGROUND
  An adverse intrauterine environment leads to permanent physiological changes including vascular tone regulation, potentially influencing the risk for adult vascular diseases. We therefore aimed to monitor responsive NOS3 expression in human umbilical artery endothelial cells (HUAEC) and to study the underlying epigenetic signatures involved in its regulation.
  
  
  RESULTS
  NOS3 and STAT3 mRNA levels were elevated in HUAEC of patients who suffered from placental insufficiency. 5-hydroxymethylcytosine, H3K9ac and Histone 2A (H2A).Zac at the NOS3 transcription start site directly correlated with NOS3 mRNA levels. Concomitantly, we observed entangled histone acetylation patterns and NOS3 response upon hypoxic conditions in vitro. Knock-down of either NOS3 or STAT3 by RNAi provided evidence for a functional NOS3/STAT3 relationship. Moreover, we recognized massive turnover of Stat3 at a discrete binding site in the NOS3 promoter. Interestingly, induced hyperacetylation resulted in short-termed increase of NOS3 mRNA followed by deferred decrease indicating that NOS3 expression could become self-attenuated by co-expressed intronic 27 nt-ncRNA. Reporter assay results and phylogenetic analyses enabled us to propose a novel model for STAT3-3'-UTR targeting by this 27-nt-ncRNA.
  
  
  CONCLUSIONS
  An adverse intrauterine environment leads to adaptive changes of NOS3 expression. Apparently, a rapid NOS3 self-limiting response upon ectopic triggers co-exists with longer termed expression changes in response to placental insufficiency involving differential epigenetic signatures. Their persistence might contribute to impaired vascular endothelial response and consequently increase the risk of cardiovascular disease later in life.
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Postberg
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Kanders
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Sakeh
authors.initials: S
authors.lastname: Forcob
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Rhea
authors.initials: R
authors.lastname: Willems
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Valerie
authors.initials: V
authors.lastname: Orth
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Kai Oliver
authors.initials: KO
authors.lastname: Hensel
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Patrick Philipp
authors.initials: PP
authors.lastname: Weil
authors.affiliation: HELIOS Childrens Hospital, Centre for Biomedical Education and Research, Witten/Herdecke University, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Wirth
authors.affiliation: Children's Hospital, Helios Klinikum Wuppertal, 42283 Wuppertal, Germany.
authors.forename: Andreas Christoph
authors.initials: AC
authors.lastname: Jenke
keywords: Intrauterine growth retardation; Nitric oxide; Placental perfusion; miRNA