title: MicroRNA and gene expression changes in unruptured human cerebral aneurysms.
abstract: OBJECTIVE The molecular mechanisms behind cerebral aneurysm formation and rupture remain poorly understood. In the past decade, microRNAs (miRNAs) have been shown to be key regulators in a host of biological processes. They are noncoding RNA molecules, approximately 21 nucleotides long, that posttranscriptionally inhibit mRNAs by attenuating protein translation and promoting mRNA degradation. The miRNA and mRNA interactions and expression levels in cerebral aneurysm tissue from human subjects were profiled. METHODS A prospective case-control study was performed on human subjects to characterize the differential expression of mRNA and miRNA in unruptured cerebral aneurysms in comparison with control tissue (healthy superficial temporal arteries [STA]). Ion Torrent was used for deep RNA sequencing. Affymetrix miRNA microarrays were used to analyze miRNA expression, whereas NanoString nCounter technology was used for validation of the identified targets. RESULTS Overall, 7 unruptured cerebral aneurysm and 10 STA specimens were collected. Several differentially expressed genes were identified in aneurysm tissue, with MMP-13 (fold change 7.21) and various collagen genes (COL1A1, COL5A1, COL5A2) being among the most upregulated. In addition, multiple miRNAs were significantly differentially expressed, with miR-21 (fold change 16.97) being the most upregulated, and miR-143-5p (fold change -11.14) being the most downregulated. From these, miR-21, miR-143, and miR-145 had several significantly anticorrelated target genes in the cohort that are associated with smooth muscle cell function, extracellular matrix remodeling, inflammation signaling, and lipid accumulation. All these processes are crucial to the pathophysiology of cerebral aneurysms. CONCLUSIONS This analysis identified differentially expressed genes and miRNAs in unruptured human cerebral aneurysms, suggesting the possibility of a role for miRNAs in aneurysm formation. Further investigation for their importance as therapeutic targets is needed.
authors.affiliation: Section of Neurosurgery and.
authors.forename: Kimon
authors.initials: K
authors.lastname: Bekelis
authors.affiliation: Dartmouth Genomics and Microarray Laboratory, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Joanna S
authors.initials: JS
authors.lastname: Kerley-Hamilton
authors.affiliation: Department of Biochemistry and Biophysics and.
authors.forename: Amy
authors.initials: A
authors.lastname: Teegarden
authors.affiliation: Dartmouth Genomics and Microarray Laboratory, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
authors.forename: Craig R
authors.initials: CR
authors.lastname: Tomlinson
authors.affiliation: Department of Biochemistry and Biophysics and.
authors.forename: Rachael
authors.initials: R
authors.lastname: Kuintzle
authors.affiliation: Section of Neurosurgery and.|Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Nathan
authors.initials: N
authors.lastname: Simmons
authors.affiliation: Section of Neurosurgery and.|Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Singer
authors.affiliation: Section of Neurosurgery and.|Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
authors.forename: David W
authors.initials: DW
authors.lastname: Roberts
authors.affiliation: MIT Computational Biology Group and.|Computer Science and Artificial Intelligence Lab, MIT, Cambridge; and.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: Manolis
authors.initials: M
authors.lastname: Kellis
authors.affiliation: Department of Biochemistry and Biophysics and.|School of Electrical Engineering and Computer Science, Oregon State University, Corvallis, Oregon.|Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
authors.forename: David A
authors.initials: DA
authors.lastname: Hendrix
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D015870:Gene Expression; D006801:Humans; D002532:Intracranial Aneurysm / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D011446:Prospective Studies; D055815:Young Adult
chemical_list: D035683:MicroRNAs
keywords: AAA = abdominal aortic aneurysm; ECM = extracellular matrix; FDR = false discovery rate; GO = Gene Ontology; PCR = polymerase chain reaction; PCT = probability of conserved target; STA = superficial temporal artery; VSMC = vascular smooth muscle cell; cerebral aneurysms; deep sequencing; gene expression; miRNA = microRNA; microRNA expression; molecular mechanisms of disease; vascular disorders