Mitotic Gene Bookmarking: An Epigenetic Program to Maintain Normal and Cancer Phenotypes

Abstract

Reconfiguration of nuclear structure and function during mitosis presents a significant challenge to resume the next cell cycle in the progeny cells without compromising structural and functional identity of the cells. Equally important is the requirement for cancer cells to retain the transformed phenotype, that is, unrestricted proliferative potential, suppression of cell phenotype, and activation of oncogenic pathways. Mitotic gene bookmarking retention of key regulatory proteins that include sequence-specific transcription factors, chromatin-modifying factors, and components of RNA Pol (RNAP) I and II regulatory machineries at gene loci on mitotic chromosomes plays key roles in coordinate control of cell phenotype, growth, and proliferation postmitotically. There is growing recognition that three distinct protein types, mechanistically, play obligatory roles in mitotic gene bookmarking: (i) Retention of phenotypic transcription factors on mitotic chromosomes is essential to sustain lineage commitment; (ii) Select chromatin modifiers and posttranslational histone modifications/variants retain competency of mitotic chromatin for gene reactivation as cells exit mitosis; and (iii) Functional components of RNAP I and II transcription complexes (e.g., UBF and TBP, respectively) are retained on genes poised for reactivation immediately following mitosis. Importantly, recent findings have identified oncogenes that are associated with target genes on mitotic chromosomes in cancer cells. The current review proposes that mitotic gene bookmarking is an extensively utilized epigenetic mechanism for stringent control of proliferation and identity in normal cells and hypothesizes that bookmarking plays a pivotal role in maintenance of tumor phenotypes, that is, unrestricted proliferation and compromised control of differentiation. Mol Cancer Res; 16(11); 1617-24. ©2018 AACR.

Figure 1:. Mitotic gene bookmarking is a broadly relevant epigenetic program for cell identity.

Studies over the past two decades have identified mitotic gene bookmarking as a broadly relevant epigenetic mechanism to coordinate cell proliferation, growth and identity in progeny cells. Several regulatory proteins and transcription factors involved in key cellular processes have been identified to bookmark target genes for post-mitotic reactivation/regulation. (A) A simplified representation of the differentiation potential of pluripotent stem cells. Only those lineages are shown for which a “master” phenotypic regulator has been identified to bookmark target genes in mitosis (labelled in red). In addition, recent findings demonstrate that key pluripotent transcription factors that include SOX2 and KLF4 mitotically bookmark genes in pluripotent stem cells. (B) Select signalling pathways, each involved in and essential for cell proliferation, growth and differentiation, are depicted. Dashed arrows represent multiple steps that are not shown for simplicity. For each pathway, downstream effectors that mitotically bookmark genes are shown in red (e.g., FOXL1, RBPJ, REX, and FISF2). (C) Accruing evidence has established key properties of chromatin of mitotically bookmark genes. Shown here are chromatin architectural proteins, cohesin (blue ring) and CTCF (red triangles), histone variants H3.3 and FI2A.Z, as well as chromatin regulators that mediate histone acetylation (e.g., p300), deposit methyl moieties on nucleosomal histones (e.g., MLL complex), methylate DNA (e.g., DNMT1), and facilitate nucleosome remodelling (e.g., lSWl).