Slow Chromatin Dynamics Allow Polycomb Target Genes to Filter Fluctuations in Transcription Factor Activity.
Genes targeted by Polycomb repressive complex 2 (PRC2) are regulated in cis by chromatin modifications and also in trans by diffusible regulators such as transcription factors. Here, we introduce a mathematical model in which transcription directly antagonizes Polycomb silencing, thereby linking these cis- and trans-regulatory inputs to gene expression. The model is parameterized by recent experimental data showing that PRC2-mediated repressive chromatin modifications accumulate extremely slowly. The model generates self-perpetuating, bistable active and repressed chromatin states that persist through DNA replication, thereby ensuring high-fidelity transmission of the current chromatin state. However, sufficiently strong, persistent activation or repression of transcription promotes switching between active and repressed chromatin states. We observe that when chromatin modification dynamics are slow, transient pulses of transcriptional activation or repression are effectively filtered, such that epigenetic memory is retained. Noise filtering thus depends on slow chromatin dynamics and may represent an important function of PRC2-based regulation.
John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Scott
S
Berry
John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
Caroline
C
Dean
John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. Electronic address: martin.howard@jic.ac.uk.
Martin
M
Howard
D002843:Chromatin / Q000378:metabolism / Q000502:physiology*; D042002:Chromatin Assembly and Disassembly; D044127:Epigenesis, Genetic; D005786:Gene Expression Regulation / Q000502:physiology; D006657:Histones / Q000378:metabolism / Q000502:physiology; D008745:Methylation; D008957:Models, Genetic; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology
D002843:Chromatin; D006657:Histones; D063151:Polycomb Repressive Complex 2
analog; bistability; chromatin; cis memory window; digital; epigenetics; histone modifications; mathematical modeling; noise filtering; transcription