Epigenetic-Mediated Regulation of Gene Expression for Biological Control and Cancer: Cell and Tissue Structure, Function, and Phenotype

Abstract

Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function is not mutually exclusive but synergistic. We explore concepts influencing the maintenance of chromatin structures, including phase separation, recognition signals, factors that mediate enhancer-promoter looping, and insulation and how these are altered during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides a potential for advancing capabilities for the diagnosis and identification of novel therapeutic targets.

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

Figure 1.. Compromised epigenetic control and higher-order chromatin organization mediate the hallmarks of cancer.

Higher-order chromatin organization supports the gene expression required for cellular identity. Interconnected with the chromosome conformation are the epigenetic states of chromatin that are critical for this genomic regulation. Dysregulation of these chromatin states in the cancer-compromised genome drive all the hallmarks of cancer including sustained proliferation, evasion of growth suppressors, resistance to cell death, enabling of replicative immortality, induction of angiogenesis, deregulation of cellular energetics, avoidance of immune destruction, tumor promoting inflammation, and genome instability and mutation.

Figure 2.. The human epigenome is organized in hierarchical, yet interdependent levels.

A hierarchy of interrelated structural and epigenetic information is not encoded within the DNA sequence, but is superimposed on this basic blueprint thereby supporting biological activity. A) PTMs of histones within active or repressed chromatin are depicted. While red circles indicate methylation, green circles indicate acetylation. DNA is methylated at CPG islands (CGI). A chromatin loop is depicted wherein a super-enhancer interacts with a promoter. B) A chromatin loop is depicted in which orange arrows indicate the directionality of CTCF motifs. At two convergent motifs a loop is formed. This loop is present in a topologically associating domain (TAD) within a phase condensate (blue circle). Anti-cancer drugs are concentrated within these phase condensates (red stars). These TADs coalesce into active A (green circle) or inactive B (red circle) compartments. At the highest-level compartments are contained within chromosome territories in the interphase nucleus. The chromatin interacts with the nuclear lamina at the nuclear periphery and at the around the nucleoli where heterochromatin in preferentially localized. Although nuclear compartments are not subdivided by membranes, the regulatory machinery for the various functions carried out by these regulatory compartments that include transcription, splicing, replication, and repair are architecturally organized in nuclear microenvironments.

Figure 3.. Chromosomes during interphase and mitotic M-phase.

a. The chromatin is present within chromosome territories during interphase. b. In prophase, the chromatin starts to condense 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 a midbody between the progeny cells, which disappears during the abscission process. g. This results in separation of the two progeny cells, which enter interphase and begin the process again.

Figure 4.. 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 to the chromatin targets. Consequently, these mechanisms result in a post-mitotic transcriptional activation after mitosis.