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Plos Genetics : Altered Dna Methylation in Leukocytes with Trisomy 21, Volume 6

By Schubeler, Dirk

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Book Id: WPLBN0003929520
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Genetics : Altered Dna Methylation in Leukocytes with Trisomy 21, Volume 6  
Author: Schubeler, Dirk
Volume: Volume 6
Language: English
Subject: Journals, Science, Genetics
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Genetics
Historic
Publication Date:
Publisher: Plos

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Schubeler, D. (n.d.). Plos Genetics : Altered Dna Methylation in Leukocytes with Trisomy 21, Volume 6. Retrieved from http://www.nationalpubliclibrary.com/


Description
Description : 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, is not well understood. We profiled DNA methylation in total peripheral blood leukocytes (PBL) and T-lymphocytes from adults with DS and normal controls and found gene-specific abnormalities of CpG methylation in DS, with many of the differentially methylated genes having known or predicted roles in lymphocyte development and function. Validation of the microarray data by bisulfite sequencing and methylationsensitive Pyrosequencing (MS-Pyroseq) confirmed strong differences in methylation (p,0.0001) for each of 8 genes tested: TMEM131, TCF7, CD3Z/CD247, SH3BP2, EIF4E, PLD6, SUMO3, and CPT1B, in DS versus control PBL. In addition, we validated differential methylation of NOD2/CARD15 by bisulfite sequencing in DS versus control T-cells. The differentially methylated genes were found on various autosomes, with no enrichment on chromosome 21. Differences in methylation were generally stable in a given individual, remained significant after adjusting for age, and were not due to altered cell counts. Some but not all of the differentially methylated genes showed different mean mRNA expression in DS versus control PBL: and the altered expression of 5 of these genes, TMEM131, TCF7, CD3Z, NOD2, and NPDC1, was recapitulated by exposing normal lymphocytes to the demethylating drug 5-aza-29deoxycytidine (5aza-dC) plus mitogens. We conclude that altered gene-specific DNA methylation is a recurrent and functionally relevant downstream response to trisomy 21 in human cells.

 

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