Parent-of-origin effects on nuclear chromatin organization and behavior in Drosophila model of Williams-Beuren Syndrome

Development of prognostic models for neuropsychiatric disorders requires careful consideration of individual 1) parent-of-origin effects (POEs) relying on 2) nuclear 3D chromatin architecture of the nerve cells and 3) epigenetic impact of miRNAs produced in parental germ cells. Drosophila can help to probe the causes and consequences leading to human neuropathology. Recently, we have developed a Drosophila model for Williams-Beuren Syndrome (WBS) a mutant agnts3 of the agnostic locus (X:11AB) harboring limk1 gene for the key enzyme of actin remodeling LIM-kinase1. The mutation agnts3 drastically increases frequency of ectopic contacts (FEC) in specific regions of intercalary heterochromatin, suppresses learning acquisition and memory formation and affects locomotion. This study reveals that in reciprocal hybrids between agnts3 and the wild type strain Berlin the polytene chromosome bands are heterogeneous in manner of FEC regulation depending either on maternal or paternal gene origin. Bioinformatic analysis demonstrates that FEC between X:11AB and the other bands of the X chromosome partly depends on short (30 bp) identical DNA fragments homologous to Drosophila 372 bp satellite DNA repeats. Although learning acquisition in conditioned courtship suppression paradigm is similar in hybrids, the middle-term memory formation shows patroclinic inheritance. Seemingly, this depends on changes in miR-974 expression levels. Several parameters of locomotion demonstrate heterosis. Our data indicate that agnts3 locus is capable of trans-regulating gene activity via POEs on chromatin nuclear organization, thereby affecting behavioral quantitative traits.

神经精神疾病预后模型的开发，需审慎考量三类核心要素：1）亲本起源效应（parent-of-origin effects, POEs）、2）神经细胞的细胞核三维染色质架构，以及3）亲本生殖细胞所产生的microRNA（miRNAs）的表观遗传影响。果蝇（Drosophila）可用于探究人类神经病理发生的诱因与结局。近期，我们构建了威廉姆斯-贝伦综合征（Williams-Beuren Syndrome, WBS）的果蝇模型：该模型基于agnostic基因座的突变体agnts3，其位于X染色体11AB区域，携带有编码肌动蛋白重塑（actin remodeling）关键酶LIM激酶1（LIM-kinase1）的limk1基因。突变体agnts3可显著提升居间异染色质（intercalary heterochromatin）特定区域的异位接触频率（frequency of ectopic contacts, FEC），抑制学习习得（learning acquisition）与记忆形成（memory formation），并影响运动能力（locomotion）。本研究发现，在agnts3突变株与野生型品系柏林（wild type strain Berlin）的正反交杂种（reciprocal hybrids）中，多线染色体带（polytene chromosome bands）的异位接触频率调控模式存在异质性，且该异质性取决于相关基因的亲本来源（母本或父本）。生物信息学分析（Bioinformatic analysis）显示，X染色体11AB区域与X染色体其他条带间的异位接触，部分依赖于长度约30bp的短DNA同源片段，该片段与果蝇372bp卫星DNA重复序列（satellite DNA repeats）同源。尽管在条件化求偶抑制范式（conditioned courtship suppression paradigm）中，杂种的学习习得能力无显著差异，但中期记忆（middle-term memory）的形成呈现父系遗传（patroclinic inheritance）特征，该现象似乎与miR-974的表达水平变化相关。部分运动能力参数表现出杂种优势（heterosis）。我们的研究数据表明，agnts3基因座可通过亲本起源效应（POEs）调控细胞核染色质组织，进而反式调控基因活性（trans-regulating gene activity），最终影响行为数量性状（behavioral quantitative traits）。