Epigenetic assimilation in the aging human brain.
BACKGROUND
Epigenetic drift progressively increases variation in DNA modification profiles of aging cells, but the finale of such divergence remains elusive. In this study, we explored the dynamics of DNA modification and transcription in the later stages of human life.


RESULTS
We find that brain tissues of older individuals (>75 years) become more similar to each other, both epigenetically and transcriptionally, compared with younger individuals. Inter-individual epigenetic assimilation is concurrent with increasing similarity between the cerebral cortex and the cerebellum, which points to potential brain cell dedifferentiation. DNA modification analysis of twins affected with Alzheimer's disease reveals a potential for accelerated epigenetic assimilation in neurodegenerative disease. We also observe loss of boundaries and merging of neighboring DNA modification and transcriptomic domains over time.


CONCLUSIONS
Age-dependent epigenetic divergence, paradoxically, changes to convergence in the later stages of life. The newly described phenomena of epigenetic assimilation and tissue dedifferentiation may help us better understand the molecular mechanisms of aging and the origins of diseases for which age is a risk factor.
Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St. R130, Toronto, Ontario, M5T 1R8, Canada.
Gabriel
G
Oh
Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St. R130, Toronto, Ontario, M5T 1R8, Canada.
Sasha
S
Ebrahimi
Institute of Systems Biology and Bioinformatics, National Central University, Chungli, 320, Taiwan.
Sun-Chong
SC
Wang
Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St. R130, Toronto, Ontario, M5T 1R8, Canada.|Department of Pediatrics, University of Chicago, Chicago, Illinois, 60637, USA.
Rene
R
Cortese
Department of Psychiatry and Behavioral Sciences, School of Medicine, Johns Hopkins University, Baltimore, Maryland, 21287, USA.
Zachary A
ZA
Kaminsky
Departments of Psychology and Psychiatry, University of Minnesota, Minneapolis, Minnesota, 55455, USA.
Irving I
II
Gottesman
Duke University Medical Center, Duke University, Box 2900, Durham, North Carolina, 27701, USA.
James R
JR
Burke
Duke University Medical Center, Duke University, Box 41, Durham, North Carolina, 27701, USA.
Brenda L
BL
Plassman
Krembil Family Epigenetics Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College St. R130, Toronto, Ontario, M5T 1R8, Canada. art.petronis@camh.ca.
Art
A
Petronis
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D005625:Frontal Lobe / Q000254:growth & development* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D014427:Twins
Aging; Alzheimer’s disease; DNA methylation; Dedifferentiation; Epigenetic drift; Epigenetics; Genomic organization; Transcriptome