Functional annotation of the human brain methylome identifies tissue-specific epigenetic variation across brain and blood.
BACKGROUND
Dynamic changes to the epigenome play a critical role in establishing and maintaining cellular phenotype during differentiation, but little is known about the normal methylomic differences that occur between functionally distinct areas of the brain. We characterized intra- and inter-individual methylomic variation across whole blood and multiple regions of the brain from multiple donors.


RESULTS
Distinct tissue-specific patterns of DNA methylation were identified, with a highly significant over-representation of tissue-specific differentially methylated regions (TS-DMRs) observed at intragenic CpG islands and low CG density promoters. A large proportion of TS-DMRs were located near genes that are differentially expressed across brain regions. TS-DMRs were significantly enriched near genes involved in functional pathways related to neurodevelopment and neuronal differentiation, including BDNF, BMP4, CACNA1A, CACA1AF, EOMES, NGFR, NUMBL, PCDH9, SLIT1, SLITRK1 and SHANK3. Although between-tissue variation in DNA methylation was found to greatly exceed between-individual differences within any one tissue, we found that some inter-individual variation was reflected across brain and blood, indicating that peripheral tissues may have some utility in epidemiological studies of complex neurobiological phenotypes.


CONCLUSIONS
This study reinforces the importance of DNA methylation in regulating cellular phenotype across tissues, and highlights genomic patterns of epigenetic variation across functionally distinct regions of the brain, providing a resource for the epigenetics and neuroscience research communities.
Institute of Psychiatry, King's College London, De Crespigny Park, London, UK.
Matthew N
MN
Davies
Manuela
M
Volta
Ruth
R
Pidsley
Katie
K
Lunnon
Abhishek
A
Dixit
Simon
S
Lovestone
Cristian
C
Coarfa
R Alan
RA
Harris
Aleksandar
A
Milosavljevic
Claire
C
Troakes
Safa
S
Al-Sarraj
Richard
R
Dobson
Leonard C
LC
Schalkwyk
Jonathan
J
Mill
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001344:Autopsy; D001482:Base Composition; D001921:Brain / Q000166:cytology*; D017124:Conserved Sequence; D018899:CpG Islands; D004247:DNA / Q000097:blood*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D053263:Gene Regulatory Networks; D015894:Genome, Human; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D009928:Organ Specificity; D010641:Phenotype; D011401:Promoter Regions, Genetic
D004247:DNA