title: Regulation of the apolipoprotein gene cluster by a long noncoding RNA.
abstract: Apolipoprotein A1 (APOA1) is the major protein component of high-density lipoprotein (HDL) in plasma. We have identified an endogenously expressed long noncoding natural antisense transcript, APOA1-AS, which acts as a negative transcriptional regulator of APOA1 both in vitro and in vivo. Inhibition of APOA1-AS in cultured cells resulted in the increased expression of APOA1 and two neighboring genes in the APO cluster. Chromatin immunoprecipitation (ChIP) analyses of a ∼50 kb chromatin region flanking the APOA1 gene demonstrated that APOA1-AS can modulate distinct histone methylation patterns that mark active and/or inactive gene expression through the recruitment of histone-modifying enzymes. Targeting APOA1-AS with short antisense oligonucleotides also enhanced APOA1 expression in both human and monkey liver cells and induced an increase in hepatic RNA and protein expression in African green monkeys. Furthermore, the results presented here highlight the significant local modulatory effects of long noncoding antisense RNAs and demonstrate the therapeutic potential of manipulating the expression of these transcripts both in vitro and in vivo.
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Halley
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA.
authors.forename: Beena M
authors.initials: BM
authors.lastname: Kadakkuzha
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA.
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Faghihi
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Magistri
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA.
authors.forename: Zane
authors.initials: Z
authors.lastname: Zeier
authors.affiliation: OPKO-CURNA, 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Khorkova
authors.affiliation: OPKO-CURNA, 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Coito
authors.affiliation: OPKO-CURNA, 10320 USA Today Way, Miramar, FL 33025, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Hsiao
authors.affiliation: RxGen, Inc., 100 Deepwood Drive, Hamden, CT 06517, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Lawrence
authors.affiliation: Center for Therapeutic Innovation, University of Miami, Miller School of Medicine, NW 10(th) Avenue, Miami, FL 33136, USA; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, NW 10(th) Avenue, Miami, FL 33136, USA. Electronic address: cwahlestedt@med.miami.edu.
authors.forename: Claes
authors.initials: C
authors.lastname: Wahlestedt
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D056945:Hep G2 Cells; D022781:Hepatocytes; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D011499:Protein Processing, Post-Translational; D016372:RNA, Antisense / Q000235:genetics / Q000378:metabolism*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D014709:Vero Cells
chemical_list: C505693:APOA1 protein, human; D016632:Apolipoprotein A-I; D006657:Histones; D016372:RNA, Antisense; D062085:RNA, Long Noncoding