Abstract
The hippocampus is a well-known target of thyroid hormone (TH; e.g., 3,5,3’-triiodothyronine—T3) and glucocorticoid (GC; e.g., corticosterone—CORT) action. Despite evidence that TH and GC play critical roles in neural development and function, few studies have identified genes and patterns of gene regulation influenced by the interaction of these hormones at a genome-wide scale. In this study we investigated gene regulation by T3, CORT, and T3 + CORT in the mouse hippocampus-derived cell line HT-22. We treated cells with T3, CORT, or T3 + CORT for 4 hr before cell harvest and RNA isolation for microarray analysis. We identified 9 genes regulated by T3, 432 genes by CORT, and 412 genes by T3 + CORT. Among the 432 CORT-regulated genes, there were 203 genes that exhibited an altered CORT response in the presence of T3, suggesting that T3 plays a significant role in modulating CORT-regulated genes. We also found 80 genes synergistically induced, and 73 genes synergistically repressed by T3 + CORT treatment. We performed in silico analysis using publicly available mouse neuronal chromatin immunoprecipitation-sequencing datasets and identified a considerable number of synergistically regulated genes with TH receptor and GC receptor peaks mapping within 1 kb of chromatin marks indicative of hormone-responsive enhancer regions. Functional annotation clustering of synergistically regulated genes reveal the relevance of proteasomal-dependent degradation, neuroprotective effect of growth hormones, and neuroinflammatory responses as key pathways to how TH and GC may coordinately influence learning and memory. Taken together, our transcriptome data represents a promising exploratory dataset for further study of common molecular mechanisms behind synergistic TH and GC gene regulation, and identify specific genes and their role in processes mediated by cross-talk between the thyroid and stress axes in a mammalian hippocampal model system.
Highlights
Thyroid hormone (TH; e.g., 3,5,3’- triiodothyronine—T3) and glucocorticoids (GCs; stress hormones; e.g., cortisol and corticosterone) are known to influence neuronal processes such as learning and memory, in part through their actions on the hippocampus
Additional clustering was performed to determine if the array signal of T3 or CORT alone regulated genes were significantly different from array signal of combined treatment with T3 + CORT
To determine if the mouse Cytochrome b561 (mCyb561) upstream Cyb561 enhancer (UCE) is transcribed into enhancer RNA (eRNA), transcripts from the UCE were measured by RTqPCR and we found that an eRNA transcribed from mCyb561 UCE was synergistically induced by combined hormone treatment (Fig 5C) similar to the pattern of hormone regulation of the Cyb561 mRNA (Fig 4J)
Summary
Thyroid hormone (TH; e.g., 3,5,3’- triiodothyronine—T3) and glucocorticoids (GCs; stress hormones; e.g., cortisol and corticosterone) are known to influence neuronal processes such as learning and memory, in part through their actions on the hippocampus. Glucocorticoids have been shown to influence hippocampal development and other hippocampal-related cognitive functions but in a context-dependent manner. Acute moderate stress has been shown to enhance memory consolidation [13,14,15], and alter long-term potentiation and synaptic plasticity depending on subfield of the hippocampus [16]. Blocking GC action in mouse hippocampal neural progenitor cells results in altered neuron developmental patterns that is accompanied by impaired memory consolidation, emphasizing the importance of GC action in the hippocampus [17]
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