Department of Molecular, Cellular and Developmental Biology, The University of Michigan, Ann Arbor, Michigan, United States of America.
National Institute of Molecular Biology and Biotechnology, University of the Philippines Diliman, Quezon City, Philippines.
PLoS One. 2019 Jul 26;14(7):e0220378. doi: 10.1371/journal.pone.0220378. eCollection 2019.
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.
海马体是甲状腺激素（TH；例如，3,5,3'-三碘甲状腺原氨酸-T3）和糖皮质激素（GC；例如，皮质酮-CORT）作用的已知靶点。尽管有证据表明 TH 和 GC 在神经发育和功能中发挥关键作用，但很少有研究确定这些激素相互作用在全基因组范围内影响的基因和基因调控模式。在这项研究中，我们研究了 T3、CORT 和 T3+CORT 在源自小鼠海马体的细胞系 HT-22 中的基因调控。我们在细胞收获和 RNA 分离进行微阵列分析前，用 T3、CORT 或 T3+CORT 处理细胞 4 小时。我们鉴定了 9 个受 T3 调节的基因、432 个受 CORT 调节的基因和 412 个受 T3+CORT 调节的基因。在 432 个 CORT 调节的基因中，有 203 个基因在存在 T3 的情况下表现出改变的 CORT 反应，表明 T3 在调节 CORT 调节的基因方面发挥重要作用。我们还发现 80 个基因协同诱导，T3+CORT 处理协同抑制 73 个基因。我们使用公开的小鼠神经元染色质免疫沉淀测序数据集进行了计算机分析，并鉴定了相当数量的协同调节基因，这些基因的 TH 受体和 GC 受体峰在 1kb 内映射到染色质标记，表明激素反应性增强子区域。协同调节基因的功能注释聚类揭示了蛋白酶体依赖性降解、生长激素的神经保护作用和神经炎症反应作为 TH 和 GC 可能协调影响学习和记忆的关键途径的相关性。总之，我们的转录组数据代表了一个有前途的探索性数据集，可进一步研究协同 TH 和 GC 基因调控背后的共同分子机制，并确定特定基因及其在哺乳动物海马模型系统中甲状腺和应激轴交叉对话介导的过程中的作用。
