AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes Journal Article

   

Authors:	Kumar, R.; Dimenna, L.; Schrode, N.; Liu, T. C.; Franck, P.; Munoz Descalzo, S.; Hadjantonakis, A. K.; Zarrin, A. A.; Chaudhuri, J.; Elemento, O.; Evans, T.
Article Title:	AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes
Abstract:	The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state. © 2013 Macmillan Publishers Limited. All rights reserved.
Keywords:	methylation; nonhuman; phenotype; animals; mice; gene targeting; gene expression; dna methylation; transcription factors; gene expression regulation; activation induced cytidine deaminase; cytidine deaminase; epigenetics; epigenesis, genetic; murinae; fibroblasts; genome; pluripotent stem cell; pluripotent stem cells; memory; antibody; nuclear reprogramming; enzyme; recombination; cell dedifferentiation; hek293 cells; null cell
Journal Title:	Nature
Volume:	500
Issue:	7460
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Date Published:	2013-08-01
Start Page:	89
End Page:	92
Language:	English
DOI:	10.1038/nature12299
PROVIDER:	scopus
PMCID:	PMC3762466
PUBMED:	23803762
DOI/URL:	http://www.scopus.com/inward/record.url?eid=2-s2.0-84881476513&partnerID=40&md5=9d32db26037787384edb3a92276bb694
Notes:	--- - "Export Date: 4 September 2013" - "CODEN: NATUA" - "Source: Scopus"

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