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Thyroid hormone may regulate mRNA abundance in liver by acting on microRNAs
Environmental Health Sciences and Research Bureau, Health Canada, Ottawa Ontario, Canada.
Environmental Health Sciences and Research Bureau, Health Canada, Ottawa Ontario, Canada.
Environmental Health Sciences and Research Bureau, Health Canada, Ottawa Ontario, Canada.
Molecular and Cellular Biology Program, University of Massachusetts, Amherst Massachusetts, United States of America.
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2010 (English)In: PLOS ONE, E-ISSN 1932-6203, Vol. 5, no 8, article id e12136Article in journal (Refereed) Published
Abstract [en]

MicroRNAs (miRNAs) are extensively involved in diverse biological processes. However, very little is known about the role of miRNAs in mediating the action of thyroid hormones (TH). Appropriate TH levels are known to be critically important for development, differentiation and maintenance of metabolic balance in mammals. We induced transient hypothyroidism in juvenile mice by short-term exposure to methimazole and perchlorate from post natal day (PND) 12 to 15. The expression of miRNAs in the liver was analyzed using Taqman Low Density Arrays (containing up to 600 rodent miRNAs). We found the expression of 40 miRNAs was significantly altered in the livers of hypothyroid mice compared to euthyroid controls. Among the miRNAs, miRs-1, 206, 133a and 133b exhibited a massive increase in expression (50- to 500-fold). The regulation of TH on the expression of miRs-1, 206, 133a and 133b was confirmed in various mouse models including: chronic hypothyroid, short-term hyperthyroid and short-term hypothyroid followed by TH supplementation. TH regulation of these miRNAs was also confirmed in mouse hepatocyte AML 12 cells. The expression of precursors of miRs-1, 206, 133a and 133b were examined in AML 12 cells and shown to decrease after TH treatment, only pre-mir-206 and pre-mir-133b reached statistical significance. To identify the targets of these miRNAs, DNA microarrays were used to examine hepatic mRNA levels in the short-term hypothyroid mouse model relative to controls. We found transcripts from 92 known genes were significantly altered in these hypothyroid mice. Web-based target predication software (TargetScan and Microcosm) identified 14 of these transcripts as targets of miRs-1, 206, 133a and 133b. The vast majority of these mRNA targets were significantly down-regulated in hypothyroid mice, corresponding with the up-regulation of miRs-1, 206, 133a and 133b in hypothyroid mouse liver. To further investigate target genes, miR-206 was over-expressed in AML 12 cells. TH treatment of cells over-expressing miR-206 resulted in decreased miR-206 expression, and a significant increase in two predicted target genes, Mup1 and Gpd2. The results suggest that TH regulation of these genes may occur secondarily via miR-206. These studies provide new insight into the role of miRNAs in mediating TH regulation of gene expression.

Place, publisher, year, edition, pages
Public Library of Science , 2010. Vol. 5, no 8, article id e12136
National Category
Environmental Sciences Cell Biology
Research subject
Enviromental Science
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URN: urn:nbn:se:oru:diva-83747DOI: 10.1371/journal.pone.0012136ISI: 000280862200005PubMedID: 20808432Scopus ID: 2-s2.0-77957911529OAI: oai:DiVA.org:oru-83747DiVA, id: diva2:1448113
Note

Funding Agencies:

Canada Genomics Research and Development Initiative  

United States Department of Health & Human Services

National Institutes of Health (NIH) - USA

NIH National Institute of Environmental Health Sciences (NIEHS) R01ES010026

Available from: 2020-06-26 Created: 2020-06-26 Last updated: 2021-06-14Bibliographically approved

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Zoeller, R. Thomas

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