Agricultural Research Organization, Volcani Center, Institute of Animal Science, Rishon LeZiyyon, 7528809, Israel.
The Robert H. Smith Faculty of Agriculture, Food and Environment, Department of Animal Science, The Hebrew University of Jerusalem, Rehovot, 76100, Israel.
Mol Psychiatry. 2019 Jul;24(7):1013-1026. doi: 10.1038/s41380-018-0280-5. Epub 2018 Oct 19.
Stressful events in early life might lead to stress resilience or vulnerability, depending on an adjustable stress-response set-point, which can be altered during postnatal sensory development and involves epigenetic regulation of corticotropin-releasing hormone (CRH). During the critical developmental period of thermal-control establishment in 3-day-old chicks, heat stress was found to affect both body temperature and expression of CRH in the hypothalamic paraventricular nucleus. Both increased during heat challenge in vulnerable chicks, whereas they decreased in resilient chicks. Our aim was to elucidate the epigenetic mechanism underlying the regulation of stress resilience or vulnerability. Accordingly, DNA CpG methylation (5mC) and hydroxymethylation (5hmC) at the CRH intron, which we found to serve as a repressor element, displayed low 5mc% alongside high 5hmc% in resilient chicks, and high 5mc% with low 5hmc% in vulnerable ones. RE1-silencing transcription factor (REST), which has a binding site on this intron, bound abundantly during acute heat stress and was nearly absent during moderate stress, restricting repression by the repressor element, and thus activating CRH gene transcription. Furthermore, REST assembled into a protein complex with TET3, which bound directly to the CRH gene. Finally, the adjacent histone recruited the histone acetylation enzyme GCN5 to this complex, which increased H3K27ac during harsh, but not moderate heat conditioning. We conclude that an epigenetic mechanism involving both post-translational histone modification and DNA methylation in a regulatory segment of CRH is involved in determining a resilient or vulnerable response to stress later in life.
早期生活中的应激事件可能导致应激弹性或脆弱性，这取决于一个可调节的应激反应设定点，该设定点可以在产后感觉发育过程中改变，并涉及促肾上腺皮质激素释放激素 (CRH) 的表观遗传调节。在 3 日龄小鸡体温控制建立的关键发育时期，热应激被发现会影响体温和下丘脑室旁核中 CRH 的表达。在脆弱的小鸡中，两者在热挑战时增加，而在有弹性的小鸡中则减少。我们的目的是阐明调节应激弹性或脆弱性的表观遗传机制。因此，我们发现作为抑制元件的 CRH 内含子中的 DNA CpG 甲基化 (5mC) 和羟甲基化 (5hmC) 在有弹性的小鸡中显示出低 5mc%和高 5hmc%，而在脆弱的小鸡中则显示出高 5mc%和低 5hmc%。RE1-沉默转录因子 (REST) 在这个内含子上有一个结合位点，在急性热应激期间大量结合，在适度应激期间几乎不存在，限制了抑制元件的抑制作用，从而激活了 CRH 基因转录。此外，REST 与直接结合 CRH 基因的 TET3 组装成一个蛋白质复合物。最后，相邻的组蛋白将组蛋白乙酰化酶 GCN5 招募到这个复合物中，该复合物在恶劣但不是适度的热条件下增加 H3K27ac。我们得出结论，涉及 CRH 调节片段中翻译后组蛋白修饰和 DNA 甲基化的表观遗传机制参与决定对生命后期应激的弹性或脆弱反应。
