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

Abstract In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of ‘reader–writer’ enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encode...

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Bibliographic Details
Published in:Nucleic acids research 2022-09, Vol.50 (16), p.9083-9104
Main Authors: Abdulla, Amith Z, Vaillant, Cédric, Jost, Daniel
Format: Article
Language:English
Subjects:
Chromatin - genetics
Chromatin - metabolism
Computational Biology
Epigenesis, Genetic
Epigenome
Epigenomics
Histones - genetics
Histones - metabolism
Humans
Life Sciences
Schizosaccharomyces - genetics
Schizosaccharomyces - metabolism
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Summary:Abstract In eukaryotes, many stable and heritable phenotypes arise from the same DNA sequence, owing to epigenetic regulatory mechanisms relying on the molecular cooperativity of ‘reader–writer’ enzymes. In this work, we focus on the fundamental, generic mechanisms behind the epigenome memory encoded by post-translational modifications of histone tails. Based on experimental knowledge, we introduce a unified modeling framework, the painter model, describing the mechanistic interplay between sequence-specific recruitment of chromatin regulators, chromatin-state-specific reader–writer processes and long-range spreading mechanisms. A systematic analysis of the model building blocks highlights the crucial impact of tridimensional chromatin organization and state-specific recruitment of enzymes on the stability of epigenomic domains and on gene expression. In particular, we show that enhanced 3D compaction of the genome and enzyme limitation facilitate the formation of ultra-stable, confined chromatin domains. The model also captures how chromatin state dynamics impact the intrinsic transcriptional properties of the region, slower kinetics leading to noisier expression. We finally apply our framework to analyze experimental data, from the propagation of γH2AX around DNA breaks in human cells to the maintenance of heterochromatin in fission yeast, illustrating how the painter model can be used to extract quantitative information on epigenomic molecular processes.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkac702