Abstract
BackgroundDysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis.ResultsUsing Next Generation Illumina sequencing methods, we sequenced hepatic small RNA libraries from baboons differing in their LDL-C response to a high-cholesterol, high-fat (HCHF) challenge diet (low LDL-C, n = 3; high LDL-C, n = 3), resulting in 517 baboon miRNAs: 490 were identical to human miRNAs and 27 were novel. We compared miRNA expression profiles from liver biopsies collected before and after the challenge diet and observed that HCHF diet elicited expression of more miRNAs compared to baseline (chow) diet for both low and high LDL-C baboons. Eighteen miRNAs exhibited differential expression in response to HCHF diet in high LDL-C baboons compared to 10 miRNAs in low LDL-C baboons. We used TargetScan/Base tools to predict putative miRNA targets; miRNAs expressed in high LDL-C baboons had significantly more gene targets than miRNAs expressed in low LDL-C responders. Further, we identified miRNA isomers and other non-coding RNAs that were differentially expressed in response to the challenge diet in both high LDL-C and low LDL-C baboons.ConclusionsWe sequenced and annotated baboon liver miRNAs from low LDL-C and high LDL-C responders using high coverage Next Gen sequencing methods, determined expression changes in response to a HCHF diet challenge, and predicted target genes regulated by the differentially expressed miRNAs. The identified miRNAs will enrich the database for non-coding small RNAs including the extent of variation in these sequences. Further, we identified other small non-coding RNAs differentially expressed in response to diet. Our discovery of differentially expressed baboon miRNAs in response to a HCHF diet challenge that differ by LDL-C phenotype is a fundamental step in understating the role of non-coding RNAs in dyslipidemia.
Highlights
Dysregulation of microRNA expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis
Annotation of small Small nucleolar RNAs (RNAs) and identification of novel miRNA genes Sequencing 12 baboon liver small RNA libraries yielded a total of 2,765,191 sequence reads with an average 230,433 reads per sample ranging from 95,728 to 441,911 reads
The proportion of expression levels of small non-coding RNAs is shown in Figure 2. miRNAs were the most abundantly expressed small RNAs in libraries from low and high low-density lipoprotein cholesterol (LDL-C) baboon livers (Figure 2a)
Summary
Dysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. Lowering LDL-C reduces the risk for atherosclerosis in humans, and modification of diet and lifestyle, and administration of drugs is a major strategy to control CVD [12]. Apart from the physiological characteristics, understanding the genetic mechanisms underlying dyslipidemia and subsequent development of atherosclerosis is fundamental to therapeutic interventions. Many genetic factors influencing risk factors for atherosclerosis have been identified [13], including genes underlying the vulnerability of arterial intimal layer to ox-LDL-C [10,14]. The expression of genes important for development of atherosclerosis is modulated by a variety of elements, including microRNAs (miRNAs)
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