Genome wide anaylsis of transcriptome modifications in rats exposed to endocrine disruptors. [RNA-Seq]

Our early life environment has a profound influence on developing organs and tissues that impacts metabolic function, and determines health and disease susceptibility across the life-course. We show an adverse early-life exposure that causes metabolic dysfunction in adulthood reprograms active and repressive histone marks in the developing liver to accelerate acquisition of an adult epigenomic signature at specific genes and chromatin states. This epigenomic reprogramming persists long after the initial exposure, but remarkably, can remain transcriptionally- and metabolically-silent until later-life exposure to a Western-style (high fat-fructose-cholesterol) diet. These findings reveal the importance of epigenome:environment interactions across the life-course, which early in life accelerate epigenomic aging and reprogram the epigenome, and later in adulthood, can unlock metabolically restriced epigenetic reprogramming to drive metabolic dysfunction.早期生命环境对发育中的器官与组织具有深远影响，可影响代谢功能，并决定个体全生命周期中的健康与疾病易感性。本研究证实，一种会导致成年期代谢功能障碍的不良早期生命暴露，可对发育中肝脏内的激活型与抑制型组蛋白修饰（histone marks）进行重编程，从而加速特定基因与染色质状态下成年表观基因组（epigenome）特征的获得。这种表观基因组重编程在初始暴露结束后仍可长期留存，但值得注意的是，其会在转录与代谢层面保持沉默，直至生命后期接触西式（高脂、高果糖、高胆固醇）饮食时才得以激活。本研究结果揭示了贯穿全生命周期的表观基因组-环境交互作用的重要性：生命早期的暴露可加速表观基因组衰老并重编程表观基因组，而成年后期的环境刺激则可解除代谢层面受限的表观遗传重编程，进而引发代谢功能障碍。