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Transgenerational effect of drug-mediated inhibition of LSD1 on eye pigment expression in Drosophila
BMC Ecology ( IF 3.368 ) Pub Date : 2020-11-23 , DOI: 10.1186/s12898-020-00330-6
Sigrid Hoyer-Fender

The Drosophila melanogaster mutant white-mottled is a well-established model for position-effect variegation (PEV). Transposition of the euchromatic white gene into the vicinity of the pericentric heterochromatin caused variegated expression of white due to heterochromatin spreading. The establishment of the euchromatin-heterochromatin boundary and spreading of silencing is regulated by mutually exclusive histone modifications, i.e. the methylations of histone H3 at lysine 9 and lysine 4. Demethylation of H3K4, catalysed by lysine-specific demethylase LSD1, is required for subsequent methylation of H3K9 to establish heterochromatin. LSD1 is therefore essential for heterochromatin formation and spreading. We asked whether drug-mediated inhibition of LSD affects the expression of white and if this induced change can be transmitted to those generations that have never been exposed to the triggering signal, i.e. transgenerational epigenetic inheritance. We used the lysine-specific demethylase 1 (LSD1)-inhibitor Tranylcypromine to investigate its effect on eye colour expression in consecutive generations by feeding the parental and F1 generations of the Drosophila melanogaster mutant white-mottled. Quantitative Western blotting revealed that Tranylcypromine inhibits H3K4-demethylation both in vitro in S2 cells as well as in embryos when used as feeding additive. Eye colour expression in male flies was determined by optical measurement of pigment extracts and qRT-PCR of white gene expression. Flies raised in the presence of Tranylcypromine and its solvent DMSO showed increased eye pigment expression. Beyond that, eye pigment expression was also affected in consecutive generations including F3, which is the first generation without contact with the inhibitor. Our results show that feeding of Tranylcypromine and DMSO caused desilencing of white in treated flies of generation F1. Consecutive generations, raised on standard food without further supplements, are also affected by the drug-induced alteration of histone modifications. Although eye pigment expression eventually returned to the basal state, the observed long-lasting effect points to a memory capacity of previous epigenomes. Furthermore, our results indicate that food compounds potentially affect chromatin modification and hence gene expression and that the alteration is putatively inherited not only parentally but transgenerationally.

中文翻译:

药物介导的LSD1抑制对果蝇眼色素表达的影响

果蝇的果蝇黑斑驳是一个完善的位置效应变异模型(PEV)。由于异染色质的扩散,常染色体白色基因向周围中心异染色质附近的转位导致白色的杂色表达。常染色质-异染色质边界的建立和沉默的扩散受相互排斥的组蛋白修饰的调控,即赖氨酸9和赖氨酸4处组蛋白H3的甲基化。赖氨酸特异性脱甲基酶LSD1催化H3K4的去甲基化,对于随后的甲基化是必需的H3K9的建立异染色质。因此,LSD1对于异染色质的形成和扩散至关重要。我们询问了药物介导的对LSD的抑制是否会影响白色的表达,以及这种诱导的变化是否可以传递给从未暴露于触发信号的那些世代,即跨代表观遗传。我们使用赖氨酸特异性脱甲基酶1(LSD1)抑制剂Tranylcypromine,通过喂饲斑驳的果蝇果蝇的亲本和F1代,研究其对连续几代对眼睛颜色表达的影响。定量蛋白质印迹显示,Tranylcypromine用作饲料添加剂时,在体外在S2细胞以及胚胎中均抑制H3K4-去甲基化。通过色素提取物的光学测量和白色基因表达的qRT-PCR确定雄性果蝇的眼睛颜色表达。在Tranylcypromine及其溶剂DMSO存在下饲养的果蝇表现出增加的眼色素表达。除此之外,包括F3在内的连续几代人的眼色素表达也受到影响,F3是不与抑制剂接触的第一代人。我们的结果表明,饲喂Tranylcypromine和DMSO会导致F1代处理过的果蝇中的白色消沉。在标准食物上连续饲养而无需进一步补充的食物,也受到药物诱导的组蛋白修饰改变的影响。尽管眼色素表达最终恢复到基础状态,但观察到的持久作用指向以前的表观基因组的记忆能力。此外,
更新日期:2020-11-23
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