Regulation of the apolipoprotein gene cluster by a long noncoding RNA

Paul Halley, BeenaM Kadakkuzha, Mohammad A Faghihi, Marco Magistri, Zane R Zeier, Olga Khorkova, Carlos Coito, Jane Hsiao, Matthew Lawrence, Claes R Wahlestedt

Research output: Contribution to journalArticle

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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 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
Pages (from-to)222-230
Number of pages9
JournalCell Reports
Volume6
Issue number1
DOIs
StatePublished - Jan 3 2014

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Long Noncoding RNA
Apolipoproteins
Apolipoprotein A-I
Multigene Family
Genes
Histones
Chromatin
Cercopithecus aethiops
Antisense RNA
Methylation
Antisense Oligonucleotides
Chromatin Immunoprecipitation
Liver
HDL Lipoproteins
Gene expression
Haplorhini
Cultured Cells
Proteins
Cells
RNA

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Regulation of the apolipoprotein gene cluster by a long noncoding RNA. / Halley, Paul; Kadakkuzha, BeenaM; Faghihi, Mohammad A; Magistri, Marco; Zeier, Zane R; Khorkova, Olga; Coito, Carlos; Hsiao, Jane; Lawrence, Matthew; Wahlestedt, Claes R.

In: Cell Reports, Vol. 6, No. 1, 03.01.2014, p. 222-230.

Research output: Contribution to journalArticle

Halley, P, Kadakkuzha, B, Faghihi, MA, Magistri, M, Zeier, ZR, Khorkova, O, Coito, C, Hsiao, J, Lawrence, M & Wahlestedt, CR 2014, 'Regulation of the apolipoprotein gene cluster by a long noncoding RNA', Cell Reports, vol. 6, no. 1, pp. 222-230. https://doi.org/10.1016/j.celrep.2013.12.015
Halley, Paul ; Kadakkuzha, BeenaM ; Faghihi, Mohammad A ; Magistri, Marco ; Zeier, Zane R ; Khorkova, Olga ; Coito, Carlos ; Hsiao, Jane ; Lawrence, Matthew ; Wahlestedt, Claes R. / Regulation of the apolipoprotein gene cluster by a long noncoding RNA. In: Cell Reports. 2014 ; Vol. 6, No. 1. pp. 222-230.
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