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However, potential age-related changes in the expression rhythmicity of clock genes and the effects of these changes on the thyroid gland remain unknown. In the present study, we evaluated the expression rhythmicity of peripheral thyroid clock genes in aged mice using RNA-seq transcriptomic analysis in young (3.5-month) versus aged (20-month) mice. In addition, we determined the cellular effects of silencing of PER2, a major clock gene regulator, in human thyroid cell lines. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that differentially expressed genes (DEGs) in the thyroid glands of aged mice were involved in mitogen-activated protein kinase (MAPK) signaling, chemokine signaling, circadian entrainment, PI3K\/AKT signaling, and Apelin signaling. The expression of circadian clock genes <jats:italic>Arntl\/Bmal1<\/jats:italic> was significantly downregulated in thyroid glands of aged mice, whereas the expression of genes involved in regulation of cell proliferation, migration, and tumorigenesis was upregulated. Peripheral thyroid clock genes, particularly <jats:italic>Per<\/jats:italic> mRNA and PER2 protein, were downregulated in the thyroid glands of aged mice, and circadian oscillation of these genes was declined. Knockdown of the circadian clock gene <jats:italic>PER2<\/jats:italic> in human thyroid follicular cells induced AP-1 activity via JNK MAPK signaling activation, which increased cell proliferation. Furthermore, the aging-related loss of <jats:italic>PER2<\/jats:italic> circadian oscillation activated the AP-1 transcription factor via the JNK MAPK pathway, which could contribute to thyroid hyperplasia, a common age-related condition.<\/jats:p>","DOI":"10.1038\/s41419-022-05342-2","type":"journal-article","created":{"date-parts":[[2022,10,26]],"date-time":"2022-10-26T03:38:45Z","timestamp":1666755525000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Loss of thyroid gland circadian PER2 rhythmicity in aged mice and its potential association with thyroid cancer development"],"prefix":"10.1038","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1477-1418","authenticated-orcid":false,"given":"Junguee","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hae Joung","family":"Sul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunsu","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0933-9321","authenticated-orcid":false,"given":"Dong Hyun","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0247-7115","authenticated-orcid":false,"given":"Minho","family":"Shong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,10,26]]},"reference":[{"key":"5342_CR1","doi-asserted-by":"publisher","first-page":"551","DOI":"10.1146\/annurev-physiol-021909-135919","volume":"72","author":"DK Welsh","year":"2010","unstructured":"Welsh DK, Takahashi JS, Kay SA. 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