Epigenetic characteristics of the mitotic chromosome in 1D and 3D

Abstract

While chromatin characteristics in interphase are widely studied, characteristics of mitotic chromatin and their inheritance through mitosis are still poorly understood. During mitosis, chromatin undergoes dramatic changes: transcription stalls, chromatin-binding factors leave the chromatin, histone modifications change and chromatin becomes highly condensed. Many key insights into mitotic chromosome state and conformation have come from extensive microscopy studies over the last century. Over the last decade, the development of 3C-based techniques has enabled the study of higher order chromosome organization during mitosis in a genome-wide manner. During mitosis, chromosomes lose their cell type-specific and locus-dependent chromatin organization that characterizes interphase chromatin and fold into randomly positioned loop arrays. Upon exit of mitosis, cells are capable of quickly rearranging the chromosome conformation to form the cell type-specific interphase organization again. The information that enables this rearrangement after mitotic exit is thought to be encoded at least in part in mitotic bookmarks, e.g. histone modifications and variants, histone remodelers, chromatin factors, and non-coding RNA. Here we give an overview of the chromosomal organization and epigenetic characteristics of interphase and mitotic chromatin in vertebrates. Second, we describe different ways in which mitotic bookmarking enables epigenetic memory of the features of interphase chromatin through mitosis. And third, we explore the role of epigenetic modifications and mitotic bookmarking in cell differentiation.

Keywords: Chromatin organization; cell cycle; epigenetic memory; epigenetics; histone modification; mitosis; mitotic bookmarking.

Figure 1

Overview of cell morphological changes, changes in the chromatin organization and changes known epigenetic characteristics during the different phases of mitosis. Hi-C data shown is in HeLa cells and was previously published in Naumova et al (2013). A color version of this figure is available online.

Figure 2

(A) Cartoon representation of chromosome territories (panel 1), compartments (panel 2), TADS (panel 3) and chromosome loops (panel 4). (B) Representation of the different chromosome organization levels in Hi-C heatmaps interphase of HeLa cell. Panel 1 shows chromosome territories in a heatmap showing all chromosomes. Panel 2 shows multiple compartments in a zoom in to the right arm of chromosome 18. Panel 3 shows a zoom in to 3.1–49.6 Mb of chromosome 18 representing multiple TADs. Panel 4 represents a possible looping interaction in a zoom in to chromosome 18 34.5–39.8 Mb. (C) Hi-C heatmaps of the same regions shown in (B) but for metaphase HeLa cells. Hi-C data shown was published in Naumova et al. (2013). (D) Model of the bottle brush polymer conformation of the mitotic chromosome suggested by Naumova et al. (2013) and Goloborodko et al (2016). A color version of this figure is available online.

Figure 3

Examples of epigenetic bookmarks in mitosis and interphase. (A) The heterochromatic mark H3K9 trimethylation is shielded by H3S10 phosphorylation caused by the Aurora B kinase during mitosis, which causes heterochromatin protein 1 (HP1) to temporarily dissociated from the mitotic chromatin. When H3S10 is dephosphorylated by the PP1γ complex, HP1 binding is restored. (B) The histone mark H3K4 di and tri methylation becomes shielded during mitotis by the H3T3 phosphorylation mark regulated by the kinase Haspin. This causes the euchromatic regulatory protein TFIID to dissociate from the chromatin. Upon mitotic exit H3T3 is dephosphorylated by the RepoMan-PP1 γ complex which restores TFIID binding to the interphase chromatin. (C) The histone acetyl transferase BRD4 can bind to histone acetylation marks in interphase and mitosis. When bound to the chromatin BRD4 can then acetylate H3K122Ac, which results in nucleosome eviction. Local nucleosome eviction enables reorganization of the nucleosome distribution and binding of big complexes like the transcription machinery. A color version of this figure is available online.

Figure 4

Mitotic bookmarks in cell differentiation. (A) Representation of the silent sister hypothesis as suggested by Falconer et al (2013). During stem cell differentiation it is believed that the daughter cells destined to be the stem cell will retain the original DNA strands of some chromosomes, where the differentiation daughter cells will mainly contain the newly replicated DNA strands. (B) Nucleosomes on one sister chromatid are specifically labelled with the H3T3 phosphorylation mark. This enables the cell to retain the sister chromatid containing to the stem cell and the other sister chromatid will be passed on to the differentiation daughter cell. A color version of this figure is available online.