Altered DNA Methylation in Leukocytes with Trisomy 21

• DOI: 10.1371/journal.pgen.1001212
• Publication Date: 2010-11-18T21:55:13Z
• Authors: Kristi Kerkel; Nicole Schupf; Kota Hatta; Deborah Pang; Martha Salas; Alexander Kratz; Mark Minden; Vundavalli Murty; Warren B. Zigman; Richard P. Mayeux; Edmund C. Jenkins; Ali Torkamani; Nicholas J. Schork; Wayne Silverman; B. Anne Croy; Benjamin Tycko
• Keywords: Trisomy; Epigenomics

The primary abnormality in Down syndrome (DS), trisomy 21, is well known; but how this chromosomal gain produces the complex DS phenotype, including immune system defects, not understood. We profiled DNA methylation total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with normal controls found gene-specific abnormalities of CpG DS, many differentially methylated genes having known or predicted roles lymphocyte development function. Validation microarray data by bisulfite sequencing methylation-sensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences (p<0.0001) for each 8 tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, CPT1B, versus control PBL. In addition, we validated differential NOD2/CARD15 T-cells. were on various autosomes, no enrichment chromosome 21. Differences generally stable a given individual, remained significant after adjusting age, due to altered cell counts. Some all showed different mean mRNA expression PBL; 5 these genes, CD3Z, NOD2, NPDC1, was recapitulated exposing lymphocytes demethylating drug 5-aza-2′deoxycytidine (5aza-dC) plus mitogens. conclude that recurrent functionally relevant downstream response 21 human cells.