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MiRNA/mRNA co-profiling identifies the miR-200 family as a central regulator of SMC quiescence.

ABSTRACT: miRNAs are versatile regulators of smooth muscle cell (SMC) fate and behavior in vascular development and disease. Targeted loss-of-function studies have established the relevance of specific miRNAs in controlling SMC differentiation or mediating phenotypic modulation. Our goal was to characterize SMC miRNAome and its contribution to transcriptome changes during phenotypic modulation. Small RNA sequencing revealed that dedifferentiation led to the differential expression of over 50 miRNAs in cultured SMC. miRNA/mRNA comparison predicted that over a third of SMC transcript expression was regulated by differentially expressed miRNAs. Our screen identified the miR-200 cluster as highly downregulated during dedifferentiation. miR-200 maintains SMC quiescence and represses proliferation, migration, and neointima formation, in part by targeting Quaking, a central SMC phenotypic switching mediator. Our study unraveled the substantial contribution of miRNAs in regulating the SMC transcriptome and identified the miR-200 cluster as a pro-quiescence mechanism and a potential inhibitor of vascular restenosis.

SUBMITTER: Du M

PROVIDER: S-EPMC9018390 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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miRNA/mRNA co-profiling identifies the miR-200 family as a central regulator of SMC quiescence.

Du Mingyuan M Espinosa-Diez Cristina C Liu Mingjun M Ahmed Ibrahim Adeola IA Mahan Sidney S Wei Jianxin J Handen Adam L AL Chan Stephen Y SY Gomez Delphine D

iScience 20220328 5

miRNAs are versatile regulators of smooth muscle cell (SMC) fate and behavior in vascular development and disease. Targeted loss-of-function studies have established the relevance of specific miRNAs in controlling SMC differentiation or mediating phenotypic modulation. Our goal was to characterize SMC miRNAome and its contribution to transcriptome changes during phenotypic modulation. Small RNA sequencing revealed that dedifferentiation led to the differential expression of over 50 miRNAs in cul ...[more]

PMID: 35465051

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Project description:BackgroundThe mechanisms underlying autoimmune thyroid disease (AITD) remain elusive. Identification of such mechanisms would reveal novel and/or better therapeutic targets. Here, we use integrated analysis of miRNAs and mRNAs expression profiling to identify potential therapeutic targets involved in the mechanisms underlying AITD.MethodsmiRNA and mRNA from twenty fresh-frozen thyroid tissues (15 from AITD patients and 5 from healthy controls) were subjected to next-generation sequencing. An anti-correlated method revealed potential pathways and disease targets, including proteins involved in the formation of primary cilia. Thus, we examined the distribution and length of primary cilia in thyroid tissues from AITD and controls using immunofluorescence and scanning electron microscopy, and parsed cilia formation in thyroid cell lines in response to inflammatory stimuli in the presence of miRNA mimics.FindingsWe found that the expression of miR-21-5p, miR-146b-3p, miR-5571-3p and miR-6503-3p was anti-correlated with Enolase 4 (ENO4), in-turned planar cell polarity protein (INTU), kinesin family member 27 (KIF27), parkin co-regulated (PACRG) and serine/threonine kinase 36 (STK36) genes. Functional classification of these miRNA/mRNAs revealed that their differential expression was associated with cilia organization. We demonstrated that the number and length of primary cilia in thyroid tissues was significantly lower in AITD than in control (frequency of follicular ciliated cells in controls = 67.54% vs a mean of 22.74% and 21.61% in HT and GD respectively p = 0.0001, by one-way ANOVA test). In addition, pro-inflammatory cytokines (IFNγ and TNFα) and specific miRNA mimics for the newly identified target genes affected cilia appearance in thyroid cell lines.InterpretationIntegrated miRNA/gene expression analysis has identified abnormal ciliogenesis as a novel susceptibility pathway that is involved in the pathogenesis of AITD. These results reflect that ciliogenesis plays a relevant role in AITD, and opens research pathways to design therapeutic targets in AITD.FundingInstituto de Salud Carlos III, Comunidad de Madrid, Grupo Español de Tumores Neuroendocrinos y Endocrinos, Ministerio de Economía y Empresa and FEDER.

Dataset Information

MiRNA/mRNA co-profiling identifies the miR-200 family as a central regulator of SMC quiescence.

Publications

miRNA/mRNA co-profiling identifies the miR-200 family as a central regulator of SMC quiescence.

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