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Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

ABSTRACT: Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet-fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.

SUBMITTER: Wagschal A

PROVIDER: S-EPMC4993048 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

Wagschal Alexandre A Najafi-Shoushtari S Hani SH Wang Lifeng L Goedeke Leigh L Sinha Sumita S deLemos Andrew S AS Black Josh C JC Ramírez Cristina M CM Li Yingxia Y Tewhey Ryan R Hatoum Ida I Shah Naisha N Lu Yong Y Kristo Fjoralba F Psychogios Nikolaos N Vrbanac Vladimir V Lu Yi-Chien YC Hla Timothy T de Cabo Rafael R de Cabo Rafael R Tsang John S JS Schadt Eric E Sabeti Pardis C PC Kathiresan Sekar S Cohen David E DE Whetstine Johnathan J Chung Raymond T RT Fernández-Hernando Carlos C Kaplan Lee M LM Bernards Andre A Gerszten Robert E RE Näär Anders M AM

Nature medicine 20151026 11

Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, ...[more]

PMID: 26501192

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Project description:BackgroundMicroRNAs (miRNAs) are small RNAs (sRNAs) approximately 21 nucleotides in length that negatively control gene expression by cleaving or inhibiting the translation of target gene transcripts. Within this context, miRNAs and siRNAs are coming to the forefront as molecular mediators of gene regulation in plant responses to annual temperature cycling and cold stress. For this reason, we chose to identify and characterize the conserved and non-conserved miRNA component of peach (Prunus persica (L.) Batsch) focusing our efforts on both the recently released whole genome sequence of peach and sRNA transcriptome sequences from two tissues representing non-dormant leaves and dormant leaf buds. Conserved and non-conserved miRNAs, and their targets were identified. These sRNA resources were used to identify cold-responsive miRNAs whose gene targets co-localize with previously described QTLs for chilling requirement (CR).ResultsAnalysis of 21 million peach sRNA reads allowed us to identify 157 and 230 conserved and non-conserved miRNA sequences. Among the non-conserved miRNAs, we identified 205 that seem to be specific to peach. Comparative genome analysis between peach and Arabidopsis showed that conserved miRNA families, with the exception of miR5021, are similar in size. Sixteen of these conserved miRNA families are deeply rooted in land plant phylogeny as they are present in mosses and/or lycophytes. Within the other conserved miRNA families, five families (miR1446, miR473, miR479, miR3629, and miR3627) were reported only in tree species (Populustrichocarpa, Citrus trifolia, and Prunus persica). Expression analysis identified several up-regulated or down-regulated miRNAs in winter buds versus young leaves. A search of the peach proteome allowed the prediction of target genes for most of the conserved miRNAs and a large fraction of non-conserved miRNAs. A fraction of predicted targets in peach have not been previously reported in other species. Several conserved and non-conserved miRNAs and miRNA-regulated genes co-localize with Quantitative Trait Loci (QTLs) for chilling requirement (CR-QTL) and bloom date (BD-QTL).ConclusionsIn this work, we identified a large set of conserved and non-conserved miRNAs and describe their evolutionary footprint in angiosperm lineages. Several of these miRNAs were induced in winter buds and co-localized with QTLs for chilling requirement and bloom date thus making their gene targets potential candidates for mediating plant responses to cold stress. Several peach homologs of genes participating in the regulation of vernalization in Arabidopsis were identified as differentially expressed miRNAs targets, potentially linking these gene activities to cold responses in peach dormant buds. The non-conserved miRNAs may regulate cellular, physiological or developmental processes specific to peach and/or other tree species.

Project description:MicroRNAs (miRNAs) are small noncoding RNAs (18-24 nt) and function in many biological processes in plants. Although Eucalyptus trees are widely planted across the world, our understanding of the miRNA regulation in the somatic embryogenesis (SE) of Eucalyptus is still poor. Here we reported, for the first time, the miRNA profiles of differentiated and dedifferentiated tissues of two Eucalyptus species and identified miRNAs involved in SE of Eucalyptus. Stem and tissue culture-induced callus were obtained from the subculture seedlings of E. camaldulensis and E. grandis x urophylla and were used as differentiated and dedifferentiated samples, respectively. Small RNA sequencing generated 304.2 million clean reads for the Eucalyptus samples (n = 3) and identified 888 miRNA precursors (197 known and 691 novel) for Eucalyptus. These miRNAs were mainly distributed in chromosomes Chr03, Chr05, and Chr08 and can produce 46 miRNA clusters. Then, we identified 327 and 343 differentially expressed miRNAs (DEmiRs) in the dedifferentiation process of E. camaldulensis and E. grandis x urophylla, respectively. DEmiRs shared by the two Eucalyptus species might be involved in the development of embryonic callus, such as MIR156, MIR159, MIR160, MIR164, MIR166, MIR169, MIR171, MIR399, and MIR482. Notably, we identified 81 upregulated and 67 downregulated miRNAs specific to E. camaldulensis, which might be associated with the high embryogenic potential. Target prediction and functional analysis showed that they might be involved in longevity regulating and plant hormone signal transduction pathways. Further, using the gene expression profiles, we observed the negative regulation of miRNA-target pairs, such as MIR160~ARF18, MIR396~GRF6, MIR166~ATHB15/HD-ZIP, and MIR156/MIR157~SPL1. Interestingly, transcription factors such as WRKY, MYB, GAMYB, TCP4, and PIL1 were found to be regulated by the DEmiRs. The genes encoding PIL1 and RPS21C, regulated by upregulated miRNAs (e.g., egd-N-miR63-5p, egd-N-miR63-5p, and MIR169,) were downregulated exclusively in the dedifferentiation of E. camaldulensis. This is the first time to study the miRNA regulation in the dedifferentiation process of Eucalyptus and it will provide a valuable resource for future studies. More importantly, it will improve our understanding of miRNA regulation during the somatic embryogenesis of Eucalyptus and benefit the Eucalyptus breeding program.

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Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

Publications

Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis.

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