Modeling epigenome folding: formation and dynamics of topologically associated chromatin domains.
Bottom Line: Remarkably, recent studies indicate that these 1D epigenomic domains tend to fold into 3D topologically associated domains forming specialized nuclear chromatin compartments.We show how experiments are fully consistent with multistable conformations where topologically associated domains of the same epigenomic state interact dynamically with each other.Our approach provides a general framework to improve our understanding of chromatin folding during cell cycle and differentiation and its relation to epigenetics.
Affiliation: Laboratoire de Physique, Ecole Normale Supérieure de Lyon, CNRS UMR 5672, Lyon 69007, France.Show MeSH
Mentions: Recent experiments performed on senescent cells have shown the nuclear rearrangement of heterochromatic marks into non-overlapping micro-domains (18). Within our formalism, this suggests that chromatin organization may relax to microphase separation configuration in non-dividing cell. Figure 5 shows the dynamic evolution of a contact map predicted by the copolymer model starting from a coil state and ending in a MPS steady-state. Interestingly, we observe the very fast formation of TADs, followed by a long period of slow compaction where long-range interactions are gradually incorporated, until the copolymer experiences a very fast transition to MPS. This intermediate slowing-down is a signature of the glassy-like dynamics of copolymers when crossing the multistability/frustrated region (35). These predictions are also consistent with recent Hi-C experiments on synchronized HeLa cells (50) showing that the formation of TADs is already achieved in early G1 starting from a mitotic conformation where the organization in TADs is apparently lost, and that the Hi-C map remains fairly unchanged throughout the cell cycle except during mitosis. This suggests that in normal dividing cells, chromatin organization converges quickly to multistable conformations and does not have the time to relax to a MPS-like state due to the periodic reinitialization of the chromatin organization at mitosis.
Affiliation: Laboratoire de Physique, Ecole Normale Supérieure de Lyon, CNRS UMR 5672, Lyon 69007, France.