Genome wide anaylsis of histone modifications in rats exposed to endocrine disruptors. [ChIP-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，进而作用于代谢功能，并决定个体在整个生命历程中的健康与疾病易感性。本研究表明，可引发成年期代谢功能障碍的不良早期暴露因素，会对发育中肝脏的激活型与抑制型组蛋白修饰（histone marks）进行重编程，从而加速特定基因及染色质状态下成年表观基因组特征的获得。这种表观基因组重编程在初始暴露结束后仍会长期存续，但值得注意的是，其在后续暴露于西式（高脂、高果糖、高胆固醇）饮食之前，可始终处于转录及代谢层面的静默状态。上述研究结果揭示了生命全程中表观基因组与环境交互作用的重要性：在生命早期，该交互作用会加速表观基因组衰老并重塑表观基因组；而在成年后期，则可解除代谢受限的表观遗传重编程状态，进而诱发代谢功能障碍。