PDF(Pubmed)
Abstract：
Switch/Sucrose Non-Fermentable (SWI/SNF)-related intellectual disability disorders (SSRIDDs) and Cornelia de Lange syndrome are rare syndromic neurodevelopmental disorders with overlapping clinical phenotypes. SSRIDDs are associated with the BAF (Brahma-Related Gene-1 Associated Factor) complex, whereas CdLS is a disorder of chromatin modification associated with the cohesin complex. Here, we used RNA interference in Drosophila melanogaster to reduce expression of six genes (brm, osa, Snr1, SMC1, SMC3, vtd) orthologous to human genes associated with SSRIDDs and CdLS. These fly models exhibit changes in sleep, activity, startle behavior (a proxy for sensorimotor integration) and brain morphology. Whole genome RNA sequencing identified 9,657 differentially expressed genes (FDR < 0.05), 156 of which are differentially expressed in both sexes in SSRIDD- and CdLS-specific analyses, including Bap60, which is orthologous to SMARCD1, a SSRIDD-associated BAF component, k-means clustering reveals genes co-regulated within and across SSRIDD and CdLS fly models. RNAi-mediated reduction of expression of six genes co-regulated with focal genes brm, osa, and/or Snr1 recapitulated changes in behavior of the focal genes. Based on the assumption that fundamental biological processes are evolutionarily conserved, Drosophila models can be used to understand underlying molecular effects of variants in chromatin-modification pathways and may aid in discovery of drugs that ameliorate deleterious phenotypic effects.
摘要：
Switch/蔗糖非发酵（SWI/SNF）相关的智力障碍（SSRIDD）和CorneliadeLange综合征是临床表型重叠的罕见综合征性神经发育障碍。SSRIDD与BAF（婆罗门相关基因-1相关因子）复合物相关，而CdLS是与粘附蛋白复合物相关的染色质修饰障碍。这里,我们在果蝇中使用RNA干扰来减少六个基因的表达(brm，osa,Snrl,SMC1，SMC3，vtd）与SSRIDD和CdLS相关的人类基因直系同源。这些苍蝇模型表现出睡眠的变化，活动,惊吓行为（感觉运动整合的代理）和大脑形态。全基因组RNA测序鉴定出9,657个差异表达基因（FDR<0.05），其中156个在SSRIDD和CdLS特异性分析中在两性中差异表达，包括与SSRIDD相关的BAF成分SMARCD1直系同源的Bap60，k-means聚类揭示了在SSRIDD和CdLS飞模型内和之间共同调节的基因。RNAi介导的六个基因的表达减少与焦点基因brm，osa,和/或Snrl概括了病灶基因的行为变化。基于基本生物过程在进化上是保守的假设，果蝇模型可用于了解染色质修饰途径中变体的潜在分子效应，并可能有助于发现改善有害表型效应的药物。
