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DNMT3L modulates significant and distinct flanking sequence preference for DNA methylation by DNMT3A and DNMT3B in vivo

热1 tlexander 添加于 2010-11-15 01:25 | 2731 次阅读 | 0 个评论

作者
Wienholz BL, Kareta MS, Moarefi AH, Gordon CA, Ginno PA, Chedin F
摘要
The DNTM3A and DNMT3B de novo DNA methyltransferases (DNMTs) are responsible for setting genomic DNA methylation patterns, a key layer of epigenetic information. Here, using an in vivo episomal methylation assay and extensive bisulfite methylation sequencing, we show that human DNMT3A and DNMT3B possess significant and distinct flanking sequence preferences for target CpG sites. Selection for high or low efficiency sites is mediated by the base composition at the -2 and +2 positions flanking the CpG site for DNMT3A, and at the -1 and +1 positions for DNMT3B. This intrinsic preference reproducibly leads to the formation of specific de novo methylation patterns characterized by up to 34-fold variations in the efficiency of DNA methylation at individual sites. Furthermore, analysis of the distribution of signature methylation hotspot and coldspot motifs suggests that DNMT flanking sequence preference has contributed to shaping the composition of CpG islands in the human genome. Our results also show that the DNMT3L stimulatory factor modulates the formation of de novo methylation patterns in two ways. First, DNMT3L selectively focuses the DNA methylation machinery on properly chromatinized DNA templates. Second, DNMT3L attenuates the impact of the intrinsic DNMT flanking sequence preference by providing a much greater boost to the methylation of poorly methylated sites, thus promoting the formation of broader and more uniform methylation patterns. This study offers insights into the manner by which DNA methylation patterns are deposited and reveals a new level of interplay between members of the de novo DNMT family.
详细资料
- 文献种类: Journal Article
- 期刊名称: PLoS Genetics
- 期刊缩写: PLoS Genet
- 期卷页: 2010年第6卷第9期
- 地址: Department of Molecular and Cellular Biology, University of California Davis, Davis, California, United States of America
- ISBN: 1553-7390
- 备注:PMID:20838592
学科领域生物医药 » 基础医学
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