Genetic and Epigenetic Alterations within Chromosome 15q11-13.3 Affect Gene Expression in Human Neurodevelopmental Disorders.

摘要

Chromosome 15q11-13 is a hotspot for genomic rearrangements, deletions, and duplications that increase risk for a variety of neurodevelopmental disorders. The most common cytogenetic causes of autism are abnormalities within chromosome 15q11-13.3, including duplication 15q syndrome (dup15q) which includes both interstitial duplications and isodicentric supernumerary chromosome 15q. The epigenetic mechanism of CpG methylation at the imprinting center of 15q controls the expression of the imprinted genes throughout the region. In addition, complex epigenetic regulation including pairing of the homologous chromosomes and long-range chromatin interactions are involved in neurodevelopmental gene regulation within 15q. In this investigation of human postmortem dup15q cortex samples compared to controls and idiopathic autism, we found further evidence that genetic disruption of the 15q locus leads to epigenetic dysregulation not necessarily predicted by copy number. In dup15q cortex, SNRPN levels were reduced, GABRB3 levels were reduced and extremely variable, and UBE3A expression positively correlated with IC methylation. Further chromatin investigations demonstrated that the IC, facilitated by MeCP2 binding, interacts with CHRNA7, forming a 7 Mb chromatin loop in a human neuronal cell line. Furthermore, reduced CHRNA7 was observed in Rett syndrome and autism cortex where MeCP2 is reduced. Determination of the epigenetic mechanisms behind the dysregulation of 15q11-13.3 expression is essential to understanding the genetic and epigenetic etiologies of dup15q, Rett syndrome and ultimately autism.