Genome folding dynamics during the M-to-G1-phase transition

During mitosis, chromatin architecture undergoes dramatic reorganization 1, 2. In prophase, the nuclear envelope breaks down, leading to mixing of nucleoplasm and cytoplasm, and chromosomes begin to condense. Cohesin ring complexes that configure interphase structural loops and link sister chromatids in G2 phase are removed, followed by chromosome segregation 3, 4. During metaphase, chromosomes are arranged into consecutive randomly positioned loop arrays, facilitated by the condensin ring complexes I and II 1, 2. This mitotic folding state occurs uniformly across all chromosomes, across cell types and species, and is locus-independent. At that time, the now-classical hallmarks of Hi-C chromosomal contact maps that are observable throughout interphase are almost entirely dissolved 1, 2. This includes A/B compartments, topologically associating domains (TADs), structural loops anchored by CTCF and cohesin, as well as loops between promoters and enhancers 1, 2, 5••, 6. However, in some studies, traces of interphase-like architectural features can be observed in mitotic cells that are not accounted for by contamination with interphase cells [5]. This suggests that mitotic chromatin organization is not entirely incompatible with the maintenance of interphase chromatin structures. The massive reorganization in chromosome architecture during mitosis as well as its uniformity across tissues has called into question whether architectural features can contribute to epigenetic memory that maintains regulatory information throughout the cell cycle [7].

Mitosis is also accompanied by loss or strong reduction in chromatin binding of a large fraction of transcription factors and their co-regulators, RNA polymerases, as well as chromatin-modifying/remodeling complexes [8]. The architectural protein CTCF is variably evicted from mitotic chromatin depending on cell type, but is rapidly rebound in anaphase 5••, 9, 10. Rebinding to chromatin of nuclear factors may influence or be influenced by architectural reorganization in newborn nuclei. However, it is important to note that not all chromatin features are lost during mitosis, as exemplified by the persistence of most histone modifications 11, 12, 13, 14, 15, chromatin accessibility at promoters and enhancers 16, 17, and a variety of DNA-binding transcription factors or cofactors 18, 19.

It is thought that the maintenance of cell identity and cellular functions necessitates the faithful restoration in G1-phase of the mutually influential processes of gene transcription and genome folding patterns 20, 21, 22, 23. This review focuses on how higher-order chromatin architecture is reshaped during the mitosis-to-G1-phase transition, and the multilayered forces that drive this reconfiguration in relation to gene transcription.

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