Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA

• APOA1 locus has an endogenously expressed natural antisense transcript
• APOA1-antisense (APOA1-AS) negatively regulates APOA1 transcription
• APOA1-AS silences target gene expression, recruiting histone modifiers
• Inhibiting APOA1-AS increases APOA1 expression in vitro and in vivo

SummaryApolipoprotein 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.

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