Theoretical analysis of epigenetic cell memory by nucleosome modification

TY - JOUR

T1 - Theoretical analysis of epigenetic cell memory by nucleosome modification

AU - Dodd, Ian B

AU - Micheelsen, Mille A

AU - Sneppen, Kim

AU - Thon, Genevieve

N1 - KEYWORDS: Cell Nucleus; Chromosomal Instability; DNA Replication; Epigenesis, Genetic; Feedback, Biochemical; Models, Biological; Nucleosomes; Schizosaccharomyces; Stochastic Processes

PY - 2007

Y1 - 2007

N2 - Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification.

AB - Chromosomal regions can adopt stable and heritable alternative states resulting in bistable gene expression without changes to the DNA sequence. Such epigenetic control is often associated with alternative covalent modifications of histones. The stability and heritability of the states are thought to involve positive feedback where modified nucleosomes recruit enzymes that similarly modify nearby nucleosomes. We developed a simplified stochastic model for dynamic nucleosome modification based on the silent mating-type region of the yeast Schizosaccharomyces pombe. We show that the mechanism can give strong bistability that is resistant both to high noise due to random gain or loss of nucleosome modifications and to random partitioning upon DNA replication. However, robust bistability required: (1) cooperativity, the activity of more than one modified nucleosome, in the modification reactions and (2) that nucleosomes occasionally stimulate modification beyond their neighbor nucleosomes, arguing against a simple continuous spreading of nucleosome modification.

U2 - 10.1016/j.cell.2007.02.053

DO - 10.1016/j.cell.2007.02.053

M3 - Journal article

C2 - 17512413

SN - 0092-8674

VL - 129

SP - 813

EP - 822

JO - Cell

JF - Cell

IS - 4

ER -