Theoretical analysis of Polycomb-Trithorax systems predicts that poised chromatin is bistable and not bivalent

• Published in: Nature communications Vol. 10; no. 1; p. 2133
• Main Authors: Sneppen, Kim, Ringrose, Leonie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.05.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 631/208/200; 631/337/100/1701; 631/337/100/2285; 631/553; 631/553/2695; Bistability; Chromatin; Chromatin - metabolism; Chromosomal Proteins, Non-Histone - metabolism; Drosophila Proteins - metabolism; Enzymes - metabolism; Epigenesis, Genetic - physiology; Gene expression; Histone Code - physiology; Histone-Lysine N-Methyltransferase - metabolism; Histones - metabolism; Humanities and Social Sciences; Mathematical models; Models, Biological; multidisciplinary; Myeloid-Lymphoid Leukemia Protein - metabolism; Nucleosomes - metabolism; Pluripotency; Polycomb group proteins; Polycomb-Group Proteins - metabolism; Science; Science (multidisciplinary); Switches; Theoretical analysis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10130-2

Polycomb (PcG) and Trithorax (TrxG) group proteins give stable epigenetic memory of silent and active gene expression states, but also allow poised states in pluripotent cells. Here we systematically address the relationship between poised, active and silent chromatin, by integrating 73 publications on PcG/TrxG biochemistry into a mathematical model comprising 144 nucleosome modification states and 8 enzymatic reactions. Our model predicts that poised chromatin is bistable and not bivalent. Bivalent chromatin, containing opposing active and silent modifications, is present as an unstable background population in all system states, and different subtypes co-occur with active and silent chromatin. In contrast, bistability, in which the system switches frequently between stable active and silent states, occurs under a wide range of conditions at the transition between monostable active and silent system states. By proposing that bistability and not bivalency is associated with poised chromatin, this work has implications for understanding the molecular nature of pluripotency. Polycomb and Trithorax group proteins regulate silent and active gene expression states, but also allow poised states in pluripotent cells. Here the authors present a mathematical model that integrates data on Polycomb/ Trithorax biochemistry into a single coherent framework which predicts that poised chromatin is not bivalent as previously proposed, but is bistable, meaning that the system switches frequently between stable active and silent states.