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

Makiko Meguro-Horike, Dag H. Yasui, Weston Powell, Diane I. Schroeder, Mitsuo Oshimura, Janine M LaSalle, Shin ichi Horike

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

Although the etiology of autism remains largely unknown, cytogenetic and genetic studies have implicated maternal copy number gains of 15q11-q13 in 1-3% of autism cases. In order to understand how maternal 15q duplication leads to dysregulation of gene expression and altered chromatin interactions, we used microcell-mediated chromosome transfer to generate a novel maternal 15q duplication model in a human neuronal cell line. Our 15q duplication neuronal model revealed that by quantitative RT-PCR, transcript levels of NDN, SNRPN, GABRB3 and CHRNA7 were reduced compared with expected levels despite having no detectable alteration in promoter DNA methylation. Since 15q11-q13 alleles have been previously shown to exhibit homologous pairing in mature human neurons, we assessed homologous pairing of 15q11-q13 by fluorescence in situ hybridization. Homologous pairing of 15q11-q13 was significantly disrupted by 15q duplication. To further understand the extent and mechanism of 15q11-q13 homologous pairing, we mapped the minimal region of homologous pairing to a ~500 kb region at the 3′ end of GABRB3 which contains multiple binding sites for chromatin regulators MeCP2 and CTCF. Both active transcription and the chromatin factors MeCP2 and CTCF are required for the homologous pairing of 15q11-q13 during neuronal maturational differentiation. These data support a model where 15q11-q13 genes are regulated epigenetically at the level of both inter- and intra-chromosomal associations and that chromosome imbalance disrupts the epigenetic regulation of genes in 15q11-q13.

Original languageEnglish (US)
Article numberddr298
Pages (from-to)3798-3810
Number of pages13
JournalHuman Molecular Genetics
Volume20
Issue number19
DOIs
StatePublished - Oct 2011

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Chromatin
Neurons
Mothers
Autistic Disorder
snRNP Core Proteins
Chromosomes
DNA Methylation
Fluorescence In Situ Hybridization
Epigenomics
Cytogenetics
Genes
Transcription Factors
Alleles
Binding Sites
Gene Expression
Cell Line
Polymerase Chain Reaction
Trisomy Chromosome 15q

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Meguro-Horike, M., Yasui, D. H., Powell, W., Schroeder, D. I., Oshimura, M., LaSalle, J. M., & Horike, S. I. (2011). Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. Human Molecular Genetics, 20(19), 3798-3810. [ddr298]. https://doi.org/10.1093/hmg/ddr298

Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. / Meguro-Horike, Makiko; Yasui, Dag H.; Powell, Weston; Schroeder, Diane I.; Oshimura, Mitsuo; LaSalle, Janine M; Horike, Shin ichi.

In: Human Molecular Genetics, Vol. 20, No. 19, ddr298, 10.2011, p. 3798-3810.

Research output: Contribution to journalArticle

Meguro-Horike, M, Yasui, DH, Powell, W, Schroeder, DI, Oshimura, M, LaSalle, JM & Horike, SI 2011, 'Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome', Human Molecular Genetics, vol. 20, no. 19, ddr298, pp. 3798-3810. https://doi.org/10.1093/hmg/ddr298
Meguro-Horike, Makiko ; Yasui, Dag H. ; Powell, Weston ; Schroeder, Diane I. ; Oshimura, Mitsuo ; LaSalle, Janine M ; Horike, Shin ichi. / Neuron-specific impairment of inter-chromosomal pairing and transcription in a novel model of human 15q-duplication syndrome. In: Human Molecular Genetics. 2011 ; Vol. 20, No. 19. pp. 3798-3810.
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