Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome

自闭症谱系疾病中最常见的反复出现的细胞遗传学异常涉及母系来源的15q11-q13染色体印迹区域的重复。因此，表征15q11-q13的表观遗传染色质组织对于理解正常神经元发育具有重要意义。在本研究中，我们重点研究了人神经细胞中15q11-q13的同源配对。我们的目的是了解15q11-q13的同源配对是如何在哺乳动物的大脑中组织的，并与配对区域内的基因表达有关。为了在神经细胞系中建立15q11-Q13母系复制模型，通过微细胞融合将人类15号染色体母系复制转移到人SH-SY5Y神经细胞中。正如预期的那样，人类神经细胞中的同源15q11-q13配对被破坏，因为人类15号染色体的额外母体拷贝。有趣的是，15q11-q13转录本的基因表达分析显示，尽管母体剂量增加，Snrpn、GABRB3、CHRNA7转录本的表达显著降低。这些结果表明，通过增加母体15q11-13剂量引起的表观遗传学变化，基因表达可能以意想不到的方式改变。

The most common recurrent cytogenetic abnormalities in autism spectrum disorders involve maternally derived duplications of the imprinted domain on chromosome 15q11-q13. Therefore characterizing the epigenetic chromatin organization of 15q11-q13 is important for understanding normal neuronal development. In this study, we focused on the homologous 15q11-q13 pairing in human neuronal cells. Our aim is to understand how the homologous pairing of 15q11-q13 is organized in the mammalian brain and associated with gene expression within the paired regions. In order to model 15q11-q13 maternal duplication in a neuronal cell line, a maternal copy of human chromosome 15 was transferred into the human SH-SY5Y neuronal cells by microcell fusion. As expected, homologous 15q11-q13 pairing was disrupted in human neuronal cells with an extra maternal copy of human chromosome 15. Interestingly, gene expression analysis of 15q11-q13 transcripts demonstrated significantly decreased expression of SNRPN, GABRB3, CHRNA7 transcripts despite increased maternal dosage. These results suggested that gene expression can be altered in unexpected ways through epigenetic changes resulting from increased maternal 15q11-13 dosage.