Bookmarking target genes in mitosis: a shared epigenetic trait of phenotypic transcription factors and oncogenes?

Abstract

The regulatory information for phenotype, proliferation, and growth of normal and tumor cells must be maintained through genome replication in the S phase and cell division during mitosis. Epigenetic mechanisms that include DNA methylation, posttranslational modifications of histones, selective utilization of histone variants, and inheritable RNA molecules play pivotal roles in maintaining cellular identity through mitotic divisions. Recent studies demonstrate that mitotic occupancy of genes, which are determinants of cell fate, growth, and proliferation, by lineage-restricted transcription factors is a key epigenetic mechanism for retention and transmission of cellular expression memory. Evidence is emerging for the presence of distinct transcriptional regulatory microenvironments in mitotic chromosomes in which the genes bookmarked for reactivation postmitotically reside. Importantly, some oncoproteins are present in mitotic microenvironments where they occupy target genes during mitosis and may contribute to perpetuating the transformed phenotype. We discuss emerging regulatory implications of epigenetically bookmarking genes during mitosis for physiologic control as well as for the onset and progression of cancer.

Figure 1. Distinct epigenetic regulatory microenvironments for gene bookmarking that are present in mitotic chromosomes

Emerging evidence suggest that mitotic chromosomes exhibit distinct epigenetic regulatory microenvironment where various mechanisms of gene bookmarking are operative. These include A) incorporation of histone H3.3 variant into genes that are bookmarked for reactivation post-mitotically, B) `incorporation of histone H2A.Z into nucleosome closer to transcription start site (TSS) and its sliding on to TSS prior to mitosis for post-mitotic expression, C) maintenance of nuclease accessible regions by cohesin where transcription factors are recruited after cell division, and 4) target gene occupancy by sequence transcription factors for post-mitotic gene activation. These microenvironments are not mutually exclusive and may function in concert with other epigenetic mechanisms (e.g., DNA methylation) for maintenance of cellular potential for lineage commitment, growth and proliferation or even disease initiation, progression and perpetuation.