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Painters in chromatin: a unified quantitative framework to systematically characterize epigenome regulation and memory.

Amith Z Abdulla, Cédric Vaillant, and Daniel Jost (2022)

Nucleic Acids Res, 50(16):9083-9104.

In eukaryotes, many stable and heritable phenotypes arise from the same DNAsequence, owing to epigenetic regulatory mechanisms relying on the molecularcooperativity of 'reader-writer' enzymes. In this work, we focus on thefundamental, generic mechanisms behind the epigenome memory encoded bypost-translational modifications of histone tails. Based on experimentalknowledge, we introduce a unified modeling framework, the painter model,describing the mechanistic interplay between sequence-specific recruitment ofchromatin regulators, chromatin-state-specific reader-writer processes andlong-range spreading mechanisms. A systematic analysis of the model buildingblocks highlights the crucial impact of tridimensional chromatin organization andstate-specific recruitment of enzymes on the stability of epigenomic domains andon gene expression. In particular, we show that enhanced 3D compaction of thegenome and enzyme limitation facilitate the formation of ultra-stable, confinedchromatin domains. The model also captures how chromatin state dynamics impactthe intrinsic transcriptional properties of the region, slower kinetics leadingto noisier expression. We finally apply our framework to analyze experimentaldata, from the propagation of γH2AX around DNA breaks in human cells to themaintenance of heterochromatin in fission yeast, illustrating how the paintermodel can be used to extract quantitative information on epigenomic molecularprocesses.

 
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