title: Trans effects of chromosome aneuploidies on DNA methylation patterns in human Down syndrome and mouse models.
abstract: BACKGROUND
  Trisomy 21 causes Down syndrome (DS), but the mechanisms by which the extra chromosome leads to deficient intellectual and immune function are not well understood.
  
  
  RESULTS
  Here, we profile CpG methylation in DS and control cerebral and cerebellar cortex of adults and cerebrum of fetuses. We purify neuronal and non-neuronal nuclei and T lymphocytes and find biologically relevant genes with DS-specific methylation (DS-DM) in each of these cell types. Some genes show brain-specific DS-DM, while others show stronger DS-DM in T cells. Both 5-methyl-cytosine and 5-hydroxy-methyl-cytosine contribute to the DS-DM. Thirty percent of genes with DS-DM in adult brain cells also show DS-DM in fetal brains, indicating early onset of these epigenetic changes, and we find early maturation of methylation patterns in DS brain and lymphocytes. Some, but not all, of the DS-DM genes show differential expression. DS-DM preferentially affected CpGs in or near specific transcription factor binding sites (TFBSs), implicating a mechanism involving altered TFBS occupancy. Methyl-seq of brain DNA from mouse models with sub-chromosomal duplications mimicking DS reveals partial but significant overlaps with human DS-DM and shows that multiple chromosome 21 genes contribute to the downstream epigenetic effects.
  
  
  CONCLUSIONS
  These data point to novel biological mechanisms in DS and have general implications for trans effects of chromosomal duplications and aneuploidies on epigenetic patterning.
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Maite
authors.initials: M
authors.lastname: Mendioroz
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA. cd2695@columbia.edu.
authors.forename: Catherine
authors.initials: C
authors.lastname: Do
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Jiang
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Chunhong
authors.initials: C
authors.lastname: Liu
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Huferesh K
authors.initials: HK
authors.lastname: Darbary
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Lang
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: John
authors.initials: J
authors.lastname: Lin
authors.affiliation: Fetal Growth and Development Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Thomas
authors.affiliation: Fetal Growth and Development Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Sayeda
authors.initials: S
authors.lastname: Abu-Amero
authors.affiliation: Fetal Growth and Development Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Philip
authors.initials: P
authors.lastname: Stanier
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Alexis
authors.initials: A
authors.lastname: Temkin
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Yale
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Meng-Min
authors.initials: MM
authors.lastname: Liu
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Salas
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA.
authors.forename: Kristi
authors.initials: K
authors.lastname: Kerkel
authors.affiliation: Department of Psychology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: George
authors.initials: G
authors.lastname: Capone
authors.affiliation: Department of Psychology, Kennedy Krieger Institute and Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Silverman
authors.affiliation: The Children's Guild Foundation Down Syndrome Research Program, Genetics Program and Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Yu
authors.affiliation: Fetal Growth and Development Group, Clinical and Molecular Genetics Unit, UCL Institute of Child Health, London, WC1N 1EH, UK.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Moore
authors.affiliation: Department of Developmental Neurobiology, New York State Institute for Basic Research in Developmental Disabilities, Staten Island, NY, 10314, USA.
authors.forename: Jerzy
authors.initials: J
authors.lastname: Wegiel
authors.affiliation: Taub Institute for Research on Alzheimer's Disease and the Aging Brain and Institute for Cancer Genetics, Columbia University Medical Center, New York, NY, 10032, USA. bt12@columbia.edu.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA. bt12@columbia.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Tycko
mesh_terms: D000328:Adult; D000782:Aneuploidy; D000818:Animals; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D005333:Fetus; D006801:Humans; D051379:Mice; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology