Regulation of the apolipoprotein gene cluster by a long noncoding RNA

Paul Halley, Beena M. Kadakkuzha, Mohammad Ali Faghihi, Marco Magistri, Zane Zeier, Olga Khorkova, Carlos Coito, Jane Hsiao, Matthew Lawrence, Claes Wahlestedt

Research output: Contribution to journalArticlepeer-review

141 Scopus citations


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 invitro and invivo. 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 invitro and invivo.

Original languageEnglish (US)
Pages (from-to)222-230
Number of pages9
JournalCell Reports
Issue number1
StatePublished - 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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