Thyroid Hormone Receptors Regulate the Expression of microRNAs with Key Roles in Skin Homeostasis

Abstract

Background: MicroRNAs (miRNAs) play a unique role in posttranscriptional regulation of gene expression and control different aspects of skin development, homeostasis, and disease. Although it is generally accepted that thyroid hormone signaling is important in skin pathophysiology, the role of their nuclear receptors (TRs) in cutaneous miRNA expression has yet to be explored. Methods: RNAseq was used to compare the skin miRnome of wild-type mice and genetically modified mice lacking both TRa1 and TRb, the main thyroid hormone binding isoforms. Changes in miRNAs with a crucial role in skin physiopathology were confirmed by stem-loop quantitative polymerase chain reaction in both total skin and isolated keratinocytes, and the levels of their target mRNAs were evaluated by real-time polymerase chain reaction. Results: The skin of TRa1/TRb knockout mice displays altered levels of >50 miRNAs. Among the downregulated species are several miRNAs, including miR-21, miR-31, miR-34, and miR-203, with crucial roles in skin homeo stasis. TRa1 appears to be the main isoform responsible for their regulation. Increased levels of gene transcripts previously shown to be bona fide targets of these miRNAs are also found in the skin and keratinocytes of TR-deficient mice. This suggests that multiple miRNAs that are downregulated in the absence of TRs cooperate to regulate gene expression in the skin. Conclusions: The miRNAs reduced in TRa1/TRb knockout mice are known to play crucial roles in epidermal proliferation, hair cycling, wound healing, stem-cell function, and tumor development, all processes altered in the absence of TRs. These results suggest that their regulation could contribute to the skin defects found in these mice and to the skin disorders associated with altered thyroid status in humans.