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Abstract
The supernumerary chromosome 21 in Down syndrome differentially affects the methylation statuses at CpG dinucleotide sites and creates genome-wide transcriptional dysregulation of parental alleles, ultimately causing diverse pathologies. At present, it is unknown whether those effects are dependent or independent of the parental origin of the nondis-joined chromosome 21. Linkage analysis is a standard method for the determination of the parental origin of this aneuploidy, although it is inadequate in cases with deficiency of samples from the progenitors. Here, we assessed the reliability of the epigenetic 5(m)CpG imprints resulting in the maternally (oocyte)-derived allele methylation at a differentially methylated region (DMR) of the candidate imprinted WRB gene for asserting the parental origin of chromosome 21. We developed a methylation-sensitive restriction enzyme-specific PCR assay, based on the WRB DMR, across single nucleotide polymorphisms (SNPs) to examine the methylation statuses in the parental alleles. In genomic DNA from blood cells of either disomic or trisomic subjects, the maternal alleles were consistently methylated, while the paternal alleles were unmethylated. However, the supernumerary chromosome 21 did alter the methylation patterns at the RUNX1 (chromosome 21) and TMEM131 (chromosome 2) CpG sites in a parent-of-origin-independent manner. To evaluate the 5(m)CpG imprints, we conducted a computational comparative epigenomic analysis of transcriptome RNA sequencing (RNA-Seq) and histone modification expression patterns. We found allele fractions consistent with the transcriptional biallelic expression of WRB and ten neighboring genes, despite the similarities in the confluence of both a 17-histone modification activation backbone module and a 5-histone modification repressive module between the WRB DMR and the DMRs of six imprinted genes. We concluded that the maternally inherited 5(m)CpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in several tissues and that trisomy 21 alters DNA methylation in parent-of-origin-dependent and -independent manners.
Keywords
MATERNAL UNIPARENTAL DISOMY, DOWN-SYNDROME, GENE-EXPRESSION, HUMAN GENOME, PATERNAL AGE, TRANSCRIPTION FACTORS, IMPRINTED GENES, SEQUENCING, DATA, STEM-CELLS, CHROMOSOME-21

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MLA
Alves da Silva, Antônio Francisco et al. “Trisomy 21 Alters DNA Methylation in Parent-of-origin-dependent and Independent Manners.” PLOS ONE 11.4 (2016): n. pag. Print.
APA
Alves da Silva, A. F., Machado, F. B., Pavarino, É. C., Biselli-Périco, J. M., Zampieri, B. L., Francisco Junior, R. da S., Mozer Rodrigues, P. T., et al. (2016). Trisomy 21 alters DNA methylation in parent-of-origin-dependent and independent manners. PLOS ONE, 11(4).
Chicago author-date
Alves da Silva, Antônio Francisco, Filipe Brum Machado, Érika Cristina Pavarino, Joice Matos Biselli-Périco, Bruna Lancia Zampieri, Ronaldo da Silva Francisco Junior, Pedro Thyago Mozer Rodrigues, et al. 2016. “Trisomy 21 Alters DNA Methylation in Parent-of-origin-dependent and Independent Manners.” Plos One 11 (4).
Chicago author-date (all authors)
Alves da Silva, Antônio Francisco, Filipe Brum Machado, Érika Cristina Pavarino, Joice Matos Biselli-Périco, Bruna Lancia Zampieri, Ronaldo da Silva Francisco Junior, Pedro Thyago Mozer Rodrigues, Douglas Terra Machado, Cíntia Barros Santos-Rebouças, Maria Gomes Fernandes, Susana Marina Chuva de Sousa Lopes, Álvaro Fabricio Lopes Rios, and Enrique Medina-Acosta. 2016. “Trisomy 21 Alters DNA Methylation in Parent-of-origin-dependent and Independent Manners.” Plos One 11 (4).
Vancouver
1.
Alves da Silva AF, Machado FB, Pavarino ÉC, Biselli-Périco JM, Zampieri BL, Francisco Junior R da S, et al. Trisomy 21 alters DNA methylation in parent-of-origin-dependent and independent manners. PLOS ONE. 2016;11(4).
IEEE
[1]
A. F. Alves da Silva et al., “Trisomy 21 alters DNA methylation in parent-of-origin-dependent and independent manners,” PLOS ONE, vol. 11, no. 4, 2016.
@article{8500621,
  abstract     = {{The supernumerary chromosome 21 in Down syndrome differentially affects the methylation statuses at CpG dinucleotide sites and creates genome-wide transcriptional dysregulation of parental alleles, ultimately causing diverse pathologies. At present, it is unknown whether those effects are dependent or independent of the parental origin of the nondis-joined chromosome 21. Linkage analysis is a standard method for the determination of the parental origin of this aneuploidy, although it is inadequate in cases with deficiency of samples from the progenitors. Here, we assessed the reliability of the epigenetic 5(m)CpG imprints resulting in the maternally (oocyte)-derived allele methylation at a differentially methylated region (DMR) of the candidate imprinted WRB gene for asserting the parental origin of chromosome 21. We developed a methylation-sensitive restriction enzyme-specific PCR assay, based on the WRB DMR, across single nucleotide polymorphisms (SNPs) to examine the methylation statuses in the parental alleles. In genomic DNA from blood cells of either disomic or trisomic subjects, the maternal alleles were consistently methylated, while the paternal alleles were unmethylated. However, the supernumerary chromosome 21 did alter the methylation patterns at the RUNX1 (chromosome 21) and TMEM131 (chromosome 2) CpG sites in a parent-of-origin-independent manner. To evaluate the 5(m)CpG imprints, we conducted a computational comparative epigenomic analysis of transcriptome RNA sequencing (RNA-Seq) and histone modification expression patterns. We found allele fractions consistent with the transcriptional biallelic expression of WRB and ten neighboring genes, despite the similarities in the confluence of both a 17-histone modification activation backbone module and a 5-histone modification repressive module between the WRB DMR and the DMRs of six imprinted genes. We concluded that the maternally inherited 5(m)CpG imprints at the WRB DMR are uncoupled from the parental allele expression of WRB and ten neighboring genes in several tissues and that trisomy 21 alters DNA methylation in parent-of-origin-dependent and -independent manners.}},
  articleno    = {{e0154108}},
  author       = {{Alves da Silva, Antônio Francisco and Machado, Filipe Brum and Pavarino, Érika Cristina and Biselli-Périco, Joice Matos and Zampieri, Bruna Lancia and Francisco Junior, Ronaldo da Silva and Mozer Rodrigues, Pedro Thyago and Machado, Douglas Terra and Santos-Rebouças, Cíntia Barros and Fernandes, Maria Gomes and Chuva de Sousa Lopes, Susana Marina and Lopes Rios, Álvaro Fabricio and Medina-Acosta, Enrique}},
  issn         = {{1932-6203}},
  journal      = {{PLOS ONE}},
  keywords     = {{MATERNAL UNIPARENTAL DISOMY,DOWN-SYNDROME,GENE-EXPRESSION,HUMAN GENOME,PATERNAL AGE,TRANSCRIPTION FACTORS,IMPRINTED GENES,SEQUENCING,DATA,STEM-CELLS,CHROMOSOME-21}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{26}},
  title        = {{Trisomy 21 alters DNA methylation in parent-of-origin-dependent and independent manners}},
  url          = {{http://dx.doi.org/10.1371/journal.pone.0154108}},
  volume       = {{11}},
  year         = {{2016}},
}

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