Kimura Ryo, Lardenoije Roy, Tomiwa Kiyotaka, Funabiki Yasuko, Nakata Masatoshi, Suzuki Shiho, Awaya Tomonari, Kato Takeo, Okazaki Shin, Murai Toshiya, Heike Toshio, Rutten Bart P F, Hagiwara Masatoshi
Department of Anatomy and Developmental Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, Germany.
Neuropsychopharmacology. 2020 Sep;45(10):1627-1636. doi: 10.1038/s41386-020-0675-2. Epub 2020 Apr 18.
Williams syndrome (WS) is a rare genetic disorder, caused by a microdeletion at the 7q11.23 region. WS exhibits a wide spectrum of features including hypersociability, which contrasts with social deficits typically associated with autism spectrum disorders. The phenotypic variability in WS likely involves epigenetic modifications; however, the nature of these events remains unclear. To better understand the role of epigenetics in WS phenotypes, we integrated DNA methylation and gene expression profiles in blood from patients with WS and controls. From these studies, 380 differentially methylated positions (DMPs), located throughout the genome, were identified. Systems-level analysis revealed multiple co-methylation modules linked to intermediate phenotypes of WS, with the top-scoring module related to neurogenesis and development of the central nervous system. Notably, ANKRD30B, a promising hub gene, was significantly hypermethylated in blood and downregulated in brain tissue from individuals with WS. Most CpG sites of ANKRD30B in blood were significantly correlated with brain regions. Furthermore, analyses of gene regulatory networks (GRNs) yielded master regulator transcription factors associated with WS. Taken together, this systems-level approach highlights the role of epigenetics in WS, and provides a possible explanation for the complex phenotypes observed in patients with WS.
威廉姆斯综合征（WS）是一种罕见的遗传性疾病，由7q11.23区域的微缺失引起。WS表现出广泛的特征，包括过度社交性，这与通常与自闭症谱系障碍相关的社交缺陷形成对比。WS的表型变异性可能涉及表观遗传修饰；然而，这些事件的本质仍不清楚。为了更好地理解表观遗传学在WS表型中的作用，我们整合了WS患者和对照组血液中的DNA甲基化和基因表达谱。通过这些研究，在整个基因组中鉴定出380个差异甲基化位点（DMP）。系统水平分析揭示了多个与WS中间表型相关的共甲基化模块，得分最高的模块与神经发生和中枢神经系统发育有关。值得注意的是，ANKRD30B是一个有前景的枢纽基因，在WS患者的血液中显著高甲基化，在脑组织中表达下调。ANKRD30B在血液中的大多数CpG位点与脑区显著相关。此外，基因调控网络（GRN）分析产生了与WS相关的主调控转录因子。综上所述，这种系统水平的方法突出了表观遗传学在WS中的作用，并为WS患者观察到的复杂表型提供了一种可能的解释。
