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. The interplay of these events in shaping cognitive phenotypes in progeny is far from clear. Simple experimental model systems such as 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. Overall design: Deep-sequencing of small RNA of wild-type and Agnts3 flies and their hybrids.