Letter

Nature 452, 215-219 (13 March 2008) | doi:10.1038/nature06745; Received 28 November 2007; Accepted 30 January 2008; Published online 17 February 2008

Shotgun bisulphite sequencing of the Arabidopsis genome reveals DNA methylation patterning

Shawn J. Cokus1,6, Suhua Feng1,2,6, Xiaoyu Zhang1,7, Zugen Chen3, Barry Merriman3, Christian D. Haudenschild4, Sriharsa Pradhan5, Stanley F. Nelson3, Matteo Pellegrini1 & Steven E. Jacobsen1,2

  1. Department of Molecular, Cell, and Developmental Biology,
  2. Howard Hughes Medical Institute,
  3. Department of Human Genetics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095, USA
  4. Illumina Inc., Hayward, California 94545, USA
  5. New England BioLabs, Ipswich, Massachusetts 01938, USA
  6. These authors contributed equally to this work.
  7. Present address: Department of Plant Biology, University of Georgia, Athens, Georgia 30602, USA.

Correspondence to: Matteo Pellegrini1Steven E. Jacobsen1,2 Correspondence and requests for materials should be addressed to S.E.J. (Email: jacobsen@ucla.edu) or M.P. (Email: matteop@mcdb.ucla.edu).

Cytosine DNA methylation is important in regulating gene expression and in silencing transposons and other repetitive sequences1, 2. Recent genomic studies in Arabidopsis thaliana have revealed that many endogenous genes are methylated either within their promoters or within their transcribed regions, and that gene methylation is highly correlated with transcription levels3, 4, 5. However, plants have different types of methylation controlled by different genetic pathways, and detailed information on the methylation status of each cytosine in any given genome is lacking. To this end, we generated a map at single-base-pair resolution of methylated cytosines for Arabidopsis, by combining bisulphite treatment of genomic DNA with ultra-high-throughput sequencing using the Illumina 1G Genome Analyser and Solexa sequencing technology6. This approach, termed BS-Seq, unlike previous microarray-based methods, allows one to sensitively measure cytosine methylation on a genome-wide scale within specific sequence contexts. Here we describe methylation on previously inaccessible components of the genome and analyse the DNA methylation sequence composition and distribution. We also describe the effect of various DNA methylation mutants on genome-wide methylation patterns, and demonstrate that our newly developed library construction and computational methods can be applied to large genomes such as that of mouse.

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