Dynamics, stability and inheritance of somatic DNA methylation imprints.

Recent research highlights the role of CpG methylation in genomic imprinting, histone and chromatin modification, transcriptional regulation, and 'gene silencing' in cancer development. An unresolved issue, however, is the role of stable inheritance of factors that manage epigenetic imprints in renewing or expanding cell populations in soma. Here we propose a mathematical model of CpG methylation that is consistent with the cooperative roles of de novo and maintenance methylation. This model describes (1) the evolution of methylation imprints toward stable, yet noisy equilibria, (2) bifurcations in methylation levels, thus the dual stability of both hypo- and hypermethylated genomic regions, and (3) sporadic transitions from hypo- to hypermethylated equilibria as a result of methylation noise in a finite system of CpG sites. Our model not only affords an explanation of the persistent coexistence of these two equilibria, but also of sporadic changes of site-specific methylation levels that may alter preset epigenetic imprints in a renewing cell population.

[1]  M. Toyota,et al.  CpG island methylator phenotypes in aging and cancer. , 1999, Seminars in cancer biology.

[2]  M. Groudine,et al.  DNA Methylation Density Influences the Stability of an Epigenetic Imprint and Dnmt3a/b-Independent De Novo Methylation , 2002, Molecular and Cellular Biology.

[3]  Lyons Mf.  The William Allan memorial award address: X-chromosome inactivation and the location and expression of X-linked genes. , 1988 .

[4]  D. Haber,et al.  DNA Methyltransferases Dnmt3a and Dnmt3b Are Essential for De Novo Methylation and Mammalian Development , 1999, Cell.

[5]  Emmanuel Tannenbaum,et al.  Evolutionary dynamics of adult stem cells: comparison of random and immortal-strand segregation mechanisms. , 2004, Physical review. E, Statistical, nonlinear, and soft matter physics.

[6]  J. Graves,et al.  A two step model for mammalian X-chromosome inactivation. , 1985, Progress in clinical and biological research.

[7]  A. Riggs,et al.  Polymerase chain reaction-aided genomic sequencing of an X chromosome-linked CpG island: methylation patterns suggest clonal inheritance, CpG site autonomy, and an explanation of activity state stability. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[8]  A. Smit.  Interspersed repeats and other mementos of transposable elements in mammalian genomes. , 1999, Current opinion in genetics & development.

[9]  Antony V. Cox,et al.  DNA Methylation Profiling of the Human Major Histocompatibility Complex: A Pilot Study for the Human Epigenome Project , 2004, PLoS biology.

[10]  V. Walbot,et al.  DNA methylation in eukaryotes: kinetics of demethylation and de novo methylation during the life cycle. , 1990, Genetics.

[11]  A. Bird.  DNA methylation and the frequency of CpG in animal DNA. , 1980, Nucleic acids research.

[12]  M. Thayer,et al.  Silencing of Mouse Aprt Is a Gradual Process in Differentiated Cells , 2003, Molecular and Cellular Biology.

[13]  Peter A. Jones,et al.  The fundamental role of epigenetic events in cancer , 2002, Nature Reviews Genetics.

[14]  A. Wolffe,et al.  DNA demethylation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[15]  J. Issa,et al.  Epigenetic changes in colorectal cancer , 2004, Cancer and Metastasis Reviews.

[16]  E. Li,et al.  Establishment and Maintenance of Genomic Methylation Patterns in Mouse Embryonic Stem Cells by Dnmt3a and Dnmt3b , 2003, Molecular and Cellular Biology.

[17]  D. Brutlag,et al.  A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Peter A. Jones,et al.  Methylation, mutation and cancer , 1992, BioEssays : news and reviews in molecular, cellular and developmental biology.

[19]  R. Roberts,et al.  Co‐operation and communication between the human maintenance and de novo DNA (cytosine‐5) methyltransferases , 2002, The EMBO journal.

[20]  A. Riggs,et al.  X-chromosome inactivation and cell memory. , 1992, Trends in genetics : TIG.

[21]  T. Mohandas,et al.  Reactivation of an inactive human X chromosome: evidence for X inactivation by DNA methylation. , 1981, Science.

[22]  S. Baylin,et al.  Aging and DNA methylation in colorectal mucosa and cancer. , 1998, Cancer research.

[23]  Brian J. Reid,et al.  Progressive Region-Specific De Novo Methylation of the p16 CpG Island in Primary Human Mammary Epithelial Cell Strains during Escape from M0 Growth Arrest , 1999, Molecular and Cellular Biology.

[24]  A. Bird.  DNA methylation patterns and epigenetic memory. , 2002, Genes & development.

[25]  S. Klimašauskas,et al.  Processive Methylation of Hemimethylated CpG Sites by Mouse Dnmt1 DNA Methyltransferase* , 2005, Journal of Biological Chemistry.

[26]  Carl T. Bergstrom,et al.  A population-epigenetic model to infer site-specific methylation rates from double-stranded DNA methylation patterns. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Cairns.  Somatic stem cells and the kinetics of mutagenesis and carcinogenesis , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  R. Scott Hansen,et al.  Hairpin-bisulfite PCR: Assessing epigenetic methylation patterns on complementary strands of individual DNA molecules , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[29]  K. Schuebel,et al.  De novo CpG island methylation in human cancer cells. , 2006, Cancer research.

[30]  Gangning Liang,et al.  Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements , 2002, Molecular and Cellular Biology.