The memory of environmental chemical exposure in C. elegans is dependent on the Jumonji demethylases jmjd-2 and jmjd-3/utx-1

How artificial environmental cues are biologically integrated and transgenerationally inherited is still poorly understood. Here, we investigate the mechanisms of inheritance of reproductive outcomes elicited by the model environmental chemical Bisphenol A (BPA) in C. elegans. We show that BPA exposure causes the derepression of an epigenetically silenced transgene in the germline for 5 generations, regardless of ancestral response. ChIP-seq, histone modifications quantitation, and immunofluorescence assays revealed that this effect is associated with a reduction of the repressive marks H3K9me3 and H3K27me3 in whole worms and in germline nuclei in the F3 as well as with reproductive dysfunctions including germline apoptosis and embryonic lethality. Furthermore, targeting of the Jumonji demethylases JMJD-2 and JMJD-3/UTX-1 restores H3K9me3 and H3K27me3 levels, respectively, and fully alleviates the BPA-induced transgenerational effects. Together, our results demonstrate the central role of repressive histone modifications in the inheritance of reproductive defects elicited by a common environmental chemical exposure. First generation C. elegans were exposed to either water, DMSO or BPA for two days, followed by collection of worm body in third generation and conduct ChIP-seq experiments.

人工环境信号如何在生物学层面被整合并实现跨代遗传，目前仍未得到充分阐释。本研究以秀丽隐杆线虫（C. elegans）为模型，探究模式环境化学品双酚A（Bisphenol A, BPA）诱发的生殖结局的跨代遗传机制。研究发现，无论亲本个体的应答情况如何，双酚A暴露可使生殖系中表观遗传沉默的转基因在连续5个世代中均发生去抑制。染色质免疫共沉淀测序（ChIP-seq）、组蛋白修饰定量及免疫荧光实验结果显示，该效应与F3代全虫及生殖系细胞核中抑制性组蛋白标记H3K9me3与H3K27me3的水平降低相关，同时还伴随生殖细胞凋亡、胚胎致死等生殖功能障碍。进一步研究表明，靶向抑制Jumonji去甲基化酶JMJD-2与JMJD-3/UTX-1，可分别恢复H3K9me3与H3K27me3的水平，并完全缓解双酚A诱发的跨代遗传效应。综上，本研究结果证实，抑制性组蛋白修饰在常见环境化学品暴露诱发的生殖缺陷跨代遗传过程中发挥核心作用。将第一代秀丽隐杆线虫分别置于水、二甲基亚砜（Dimethyl sulfoxide, DMSO）或双酚A环境中暴露2天，随后收集第三代线虫的虫体并开展染色质免疫共沉淀测序实验。