Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues.
DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. Here, we show that methylation patterns within populations of cells from individual somatic tissues are heterogeneous and polymorphic. Using in vitro evolution of immortalized fibroblasts for over 300 generations, we track the dynamics of polymorphic methylation at regions developing significant differential methylation on average. The data indicate that changes in population-averaged methylation occur through a stochastic process that generates a stream of local and uncorrelated methylation aberrations. Despite the stochastic nature of the process, nearly deterministic epigenetic remodeling emerges on average at loci that lose or gain resistance to methylation accumulation. Changes in the susceptibility to methylation accumulation are correlated with changes in histone modification and CTCF occupancy. Characterizing epigenomic polymorphism within cell populations is therefore critical to understanding methylation dynamics in normal and cancer cells.
Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel.
Gilad
G
Landan
Netta Mendelson
NM
Cohen
Zohar
Z
Mukamel
Amir
A
Bar
Alina
A
Molchadsky
Ran
R
Brosh
Shirley
S
Horn-Saban
Daniela Amann
DA
Zalcenstein
Naomi
N
Goldfinger
Adi
A
Zundelevich
Einav Nili
EN
Gal-Yam
Varda
V
Rotter
Amos
A
Tanay
D001483:Base Sequence; D000076246:CCCTC-Binding Factor; D018899:CpG Islands; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014407:Tumor Cells, Cultured
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D012097:Repressor Proteins