title: Dynamic and static maintenance of epigenetic memory in pluripotent and somatic cells.
abstract: Stable maintenance of gene regulatory programs is essential for normal function in multicellular organisms. Epigenetic mechanisms, and DNA methylation in particular, are hypothesized to facilitate such maintenance by creating cellular memory that can be written during embryonic development and then guide cell-type-specific gene expression. Here we develop new methods for quantitative inference of DNA methylation turnover rates, and show that human embryonic stem cells preserve their epigenetic state by balancing antagonistic processes that add and remove methylation marks rather than by copying epigenetic information from mother to daughter cells. In contrast, somatic cells transmit considerable epigenetic information to progenies. Paradoxically, the persistence of the somatic epigenome makes it more vulnerable to noise, since random epimutations can accumulate to massively perturb the epigenomic ground state. The rate of epigenetic perturbation depends on the genomic context, and, in particular, DNA methylation loss is coupled to late DNA replication dynamics. Epigenetic perturbation is not observed in the pluripotent state, because the rapid turnover-based equilibrium continuously reinforces the canonical state. This dynamic epigenetic equilibrium also explains how the epigenome can be reprogrammed quickly and to near perfection after induced pluripotency.
authors.affiliation: 1] Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2].
authors.forename: Zohar
authors.initials: Z
authors.lastname: Shipony
authors.affiliation: 1] Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2].
authors.forename: Zohar
authors.initials: Z
authors.lastname: Mukamel
authors.affiliation: Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Netta Mendelson
authors.initials: NM
authors.lastname: Cohen
authors.affiliation: Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Gilad
authors.initials: G
authors.lastname: Landan
authors.affiliation: 1] Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel [2] Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elad
authors.initials: E
authors.lastname: Chomsky
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Shlomit Reich
authors.initials: SR
authors.lastname: Zeliger
authors.affiliation: Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Yael Chagit
authors.initials: YC
authors.lastname: Fried
authors.affiliation: Department of Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Elena
authors.initials: E
authors.lastname: Ainbinder
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Nir
authors.initials: N
authors.lastname: Friedman
authors.affiliation: Department of Computer Science and Applied Mathematics, and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Amos
authors.initials: A
authors.lastname: Tanay
mesh_terms: D000483:Alleles; D002460:Cell Line; D045744:Cell Line, Tumor; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D019175:DNA Methylation; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*