Loss of thyroid gland circadian PER2 rhythmicity in aged mice and its potential association with thyroid cancer development

Abstract

Molecular clocks operate in peripheral tissues, including endocrine glands, and play important regulatory roles in this context. 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 Arntl/Bmal1 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 Per 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 PER2 in human thyroid follicular cells induced AP-1 activity via JNK MAPK signaling activation, which increased cell proliferation. Furthermore, the aging-related loss of PER2 circadian oscillation activated the AP-1 transcription factor via the JNK MAPK pathway, which could contribute to thyroid hyperplasia, a common age-related condition.

Cellular iron depletion enhances behavioral rhythm by limiting brain Per1 expression in mice

“…The circadian rhythm is produced and regulated by the so‐called “clock” genes. In the feedback loop composed by clock genes and their encoded proteins, the BMAL1/CLOCK complex acts as a transcriptional activator of the genes encoding the repressor proteins, PER1 and PER2 32,33 . In the present study, we examined the expression of PER1, CLOCK, and BMAL1 to investigate whether the decreased brain iron in Fpn1 Cdh5 ‐cKO mice could impact the levels of these proteins.…”

The role of circadian clock in regulating cell functions: implications for diseases

“…In glioblastoma, deletion of Clock or its target gene OLFML3 (a microglia‐attracting chemokine) decreases intratumoral microglia infiltration in the tumor microenvironment and increases overall survival 76 . Pathogen recognition receptors, a group of innate immune receptors, serve as upstream regulators of cytokines/chemokines such as IL‐1, TNF‐α, and IL‐6 through shared signaling modules including NF‐κB, activator protein‐1 (AP‐1), and MAPK, 77 and regulation of NF‐κB, AP‐1, and MAPK by circadian clocks may contribute to the diurnal variations of cytokines/chemokines 78–80 …”

“… 76 Pathogen recognition receptors, a group of innate immune receptors, serve as upstream regulators of cytokines/chemokines such as IL‐1, TNF‐α, and IL‐6 through shared signaling modules including NF‐κB, activator protein‐1 (AP‐1), and MAPK, 77 and regulation of NF‐κB, AP‐1, and MAPK by circadian clocks may contribute to the diurnal variations of cytokines/chemokines. 78 , 79 , 80 …”

Circle(s) of Life: The Circadian Clock from Birth to Death

“…Downstream of the SCN, peripheral clocks are also disturbed in the elderly ( Figure 3 ). Transcriptional rhythms of multiple organs have been reported as attenuated in aged patients and mice, including ovaries [ 238 ], thyroid [ 239 ], skeletal and vascular muscle [ 240 ] and kidneys [ 241 ]. Some of those peripheral clock rhythms could potentially be restored by timed exercise [ 240 , 241 ].…”

“…Studies in mice show that voluntary wheel running can restore dysfunctions in activity rhythms in older mice, and there seems to be a sex difference in this response, as older females run significantly longer distances than males [ 242 ]. Surprisingly, some of these studies show a relative retention of liver rhythms [ 238 , 239 ], while another study conducted in rats suggest that changes in liver circadian genes during aging might be characteristic of males [ 243 ].…”