Regulation of the Apolipoprotein Gene Cluster by a Long Noncoding RNA

Abstract

Apolipoprotein A-1 (APOA1) is the major protein component of high-density lipoprotein (HDL) in plasma. We have identified an endogenously expressed long non-coding 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 ~50Kb 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 using 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. The results presented here further highlight the significant local modulatory effects of long non-coding antisense RNAs, and demonstrate the therapeutic potential of manipulating the expression of these transcripts both in vitro and in vivo.

Long Noncoding RNAs in Atherosclerosis

“…SENCR knockdown decreased myocardin al 72) identified a dendritic cell-specific lncRNA termed lnc-DC playing a critical role in the differentiation of dendritic cells from human monocytes and mouse bone marrow, a cell type playing important roles in atherosclerosis 73) . Another study has shown that lncRNA APOA1-AS function as a negative transcriptional regulator and distinct histone methylation patterns modulator of APOA1 74) , a major component of HDL particles associated with reduced atherosclerosis 75) . Former studies in human atherosclerotic plaques and carotid artery injury model of rat identified that lncRNA H19 is re-expressed 76,77) .…”

Evaluation of the Apo Lipoprot E in - A1 Levels in Type Ii Diabetes Mellitus, With and Without Cad

“…And, a recent report suggests that apo A-1 mRNA is regulated by endogenously expressed antisense RNA. 13 Several reports, however, indicate that apo A-1 levels are positively associated with increased risk of macro vascular disease and may represent an independent risk factor for CAD. 14 Also, decreased apo A-1/HDL absolute production rate could also be the cause for incidence of CAD.…”

C1QBP is upregulated in colon cancer and binds to apolipoprotein A-I

“…Moreover, ApoA-I is a major component of high-density lipoprotein in plasma, which exerts protective anti-inflammatory, anti-oxidant and anti-microbial functions, and it is important in innate immunity (21). ApoA-I is synthesized primarily in the liver (80%) and small intestine (10%) (24), and it is known to be important in reverse cholesterol transport and for promoting cholesterol efflux from tissues by acting as a cofactor for lecithin cholesterol acyltransferase (24). In a study of a cohort of >520,000 participants from 10 European countries, high serum concentrations of HDL and ApoA-I were associated with a decreased risk of colon cancer (23).…”