Tissue-specific variation in DNA methylation levels along human chromosome 1.
BACKGROUND
DNA methylation is a major epigenetic modification important for regulating gene expression and suppressing spurious transcription. Most methods to scan the genome in different tissues for differentially methylated sites have focused on the methylation of CpGs in CpG islands, which are concentrations of CpGs often associated with gene promoters.


RESULTS
Here, we use a methylation profiling strategy that is predominantly responsive to methylation differences outside of CpG islands. The method compares the yield from two samples of size-selected fragments generated by a methylation-sensitive restriction enzyme. We then profile nine different normal tissues from two human donors relative to spleen using a custom array of genomic clones covering the euchromatic portion of human chromosome 1 and representing 8% of the human genome. We observe gross regional differences in methylation states across chromosome 1 between tissues from the same individual, with the most striking differences detected in the comparison of cerebellum and spleen. Profiles of the same tissue from different donors are strikingly similar, as are the profiles of different lobes of the brain. Comparing our results with published gene expression levels, we find that clones exhibiting extreme ratios reflecting low relative methylation are statistically enriched for genes with high expression ratios, and vice versa, in most pairs of tissues examined.


CONCLUSIONS
The varied patterns of methylation differences detected between tissues by our methylation profiling method reinforce the potential functional significance of regional differences in methylation levels outside of CpG islands.
De Bustos
Cecilia
C
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.|Current address: United Nations World Food Programme, Lima, Peru.
Ramos
Edward
E
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington, Seattle, Washington, USA.|Current address: National Institutes of Health, Bethesda Maryland, USA.
Young
Janet M
JM
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Tran
Robert K
RK
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Current address: Genome Center, University of California at Davis, Davis, California, USA.
Menzel
Uwe
U
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Langford
Cordelia F
CF
The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK.
Eichler
Evan E
EE
Department of Genome Sciences, University of Washington, Seattle, Washington, USA.|Howard Hughes Medical Institute, Seattle, Washington, USA.
Hsu
Li
L
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Henikoff
Steve
S
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Howard Hughes Medical Institute, Seattle, Washington, USA.
Dumanski
Jan P
JP
Department of Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
Trask
Barbara J
BJ
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Department of Genome Sciences, University of Washington, Seattle, Washington, USA.