Abstract
Experiments have shown that in embryonic stem cells, the promoters of many lineage-control genes contain “bivalent domains”, within which the nucleosomes possess both active (H3K4me3) and repressive (H3K27me3) marks. Such bivalent modifications play important roles in maintaining pluripotency in embryonic stem cells. Here, to investigate gene expression dynamics when there are regulations in bivalent histone modifications and random partition in cell divisions, we study how positive feedback to histone methylation/demethylation controls the transition dynamics of the histone modification patterns along with cell cycles. We constructed a computational model that includes dynamics of histone marks, three-stage chromatin state transitions, transcription and translation, feedbacks from protein product to enzymes to regulate the addition and removal of histone marks, and the inheritance of nucleosome state between cell cycles. The model reveals how dynamics of both nucleosome state transition and gene expression are dependent on the enzyme activities and feedback regulations. Results show that the combination of stochastic histone modification at each cell division and the deterministic feedback regulation work together to adjust the dynamics of chromatin state transition in stem cell regenerations.
Highlights
In eukaryotic cells, most DNA sequences are enclosed into basic organizational chromatin units–nucleosomes
Our model describes the stochastic chromatin dynamics that involve both stochastic kinetics in histone modifications and random partitions in cell division
This study developed a computational model of gene expression with a positive feedback through the regulation of nucleosome state transitions
Summary
Most DNA sequences are enclosed into basic organizational chromatin units–nucleosomes. Histone N-termini (tails) can undergo diverse post-translational covalent modifications, including acetylation, phosphorylation, methylation, ubiquitination and ADP-ribosylation[13]; these modifications can lead to either active or repressive gene expression activities.[2,11] A dynamic equilibrium of histone modifications can be attained due to the balance between various enzymes that are associated with the addition and removal of covalent marks
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