How the cell cycle impacts chromatin architecture and influences cell fate

Abstract

Since the earliest observations of cells undergoing mitosis, it has been clear that there is an intimate relationship between the cell cycle and nuclear chromatin architecture. The nuclear envelope and chromatin undergo robust assembly and disassembly during the cell cycle, and transcriptional and post-transcriptional regulation of histone biogenesis and chromatin modification is controlled in a cell cycle-dependent manner. Chromatin binding proteins and chromatin modifications in turn influence the expression of critical cell cycle regulators, the accessibility of origins for DNA replication, DNA repair, and cell fate. In this review we aim to provide an integrated discussion of how the cell cycle machinery impacts nuclear architecture and vice-versa. We highlight recent advances in understanding cell cycle-dependent histone biogenesis and histone modification deposition, how cell cycle regulators control histone modifier activities, the contribution of chromatin modifications to origin firing for DNA replication, and newly identified roles for nucleoporins in regulating cell cycle gene expression, gene expression memory and differentiation. We close with a discussion of how cell cycle status may impact chromatin to influence cell fate decisions, under normal contexts of differentiation as well as in instances of cell fate reprogramming.

Keywords: cell cycle; chromatin; histones; mitosis; nucleoporins.

FIGURE 1

Major features of chromatin and nuclear changes during the cell cycle. Cells in G1 phase exhibit subnuclear domains with some regions associated with nuclear pores and nuclear lamina. Pre-RCs preferentially form at accessible chromatin. During S-phase histones are transcribed and synthesized, DNA is replicated and new (light green) and recycled (dark green) nucleosomes assemble to form nascent chromatin. PTM writers and readers also associate with nascent chromatin. During G2 nucleosomes mature and histone biogenesis is inhibited. During mitosis, chromosomes condense and many transcription factors and chromatin binding proteins are ejected from the chromatin. The nuclear envelope breaks down disrupting nuclear lamina associated domains. Illustration by Nicole Ethen.

FIGURE 2

Chromatin modifications and histone biogenesis regulators during the cell cycle. (A) Factors controlling histone biogenesis are regulated by the cell cycle to limit histone biogenesis to S-phase. (B) Chromatin modifications, including histone PTMs and 5-hydroxy-methylcytosine (5hMe) occur in a cell cycle regulated manner to impact gene expression and nuclear architecture.