Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Fidelity of Mechanisms Governing the Cell Cycle

Abstract

The cell cycle is governed by stringent epigenetic mechanisms that, in response to intrinsic and extrinsic regulatory cues, support fidelity of DNA replication and cell division. We will focus on (1) the complex and interdependent processes that are obligatory for control of proliferation and compromised in cancer, (2) epigenetic and topological domains that are associated with distinct phases of the cell cycle that may be altered in cancer initiation and progression, and (3) the requirement for mitotic bookmarking to maintain intranuclear localization of transcriptional regulatory machinery to reinforce cell identity throughout the cell cycle to prevent malignant transformation.

Keywords: Cell cycle control; Chromatin; Epigenetic control; Histones; Mitotic gene bookmarking; Nuclear structure; Nucleosomes; Transcription; Tumor suppression.

Figure 1.. Chromosomes during interphase and mitotic M-phase.

a. The chromatin is present within chromosome territories during interphase. b. In prophase, the chromatin condenses into chromosomes and the nucleolus disappears. Centrosomes migrate to the opposite poles of the nucleus and initiate the formation of the mitotic spindle. c. During prometaphase-metaphase, the nuclear envelope breaks. Then, the chromosomes are oriented and aligned on the metaphase plate. d. In early anaphase, the sister chromatids separate, and the microtubules pull the chromatids apart toward the two opposite poles of the mitotic spindle. d• In late anaphase, the plasma membrane begins to invaginate to the equatorial plane. e. During telophase, the plasma membrane continues to invaginate, and the chromosomes decondense. f. During cytokinesis-abscission, the invagination of the plasma membrane appears through a contractile ring. The cleavage furrow progresses to create midbody between the progeny cells, which disappears during the abscission process. g. This results in the separation of the two progeny cells, which enter interphase and begin the process again.

Figure 2.. Mitotic bookmarking establishes post-mitotic reactivation of gene expression.

During mitosis, histone marks and chromatin regulators bind the open regions on the chromatin, thus bookmarking specific loci for the memory program. Transcription factors can additionally associate with the chromatin targets. Consequently, these mechanisms result in a post-mitotic transcriptional activation after mitosis.