Architectural epigenetics: mitotic retention of mammalian transcriptional regulatory information

Abstract

Epigenetic regulatory information must be retained during mammalian cell division to sustain phenotype-specific and physiologically responsive gene expression in the progeny cells. Histone modifications, DNA methylation, and RNA-mediated silencing are well-defined epigenetic mechanisms that control the cellular phenotype by regulating gene expression. Recent results suggest that the mitotic retention of nuclease hypersensitivity, selective histone marks, as well as the lineage-specific transcription factor occupancy of promoter elements contribute to the epigenetic control of sustained cellular identity in progeny cells. We propose that these mitotic epigenetic signatures collectively constitute architectural epigenetics, a novel and essential mechanism that conveys regulatory information to sustain the control of phenotype and proliferation in progeny cells by bookmarking genes for activation or suppression.

FIG. 1.

Mechanisms of inheritable epigenetics. Mammalian gene expression is tightly controlled by genetic as well as epigenetic mechanisms. Epigenetics modifies the phenotype without altering the genotype of a cell. Shown here are some well-defined epigenetic mechanisms that include histone modifications, DNA methylation, and the noncoding RNA-mediated modulation of gene expression. Some of these mechanisms are inheritable through successive cell divisions and contribute to the maintenance of cellular phenotype. Recent studies show that the association of components of transcriptional regulatory machinery with target genes on mitotic chromosomes is a novel epigenetic mechanism that poises genes involved in key cellular processes, such as growth, proliferation, and lineage commitment, for expression in progeny cells.

FIG. 2.

Gene bookmarking: the retention of transcriptional regulatory machinery with target genes on mitotic chromosomes. Mitotic chromosomes represent tightly packed, transcriptionally repressed chromatin and are characteristically resistant to nuclease accessibility. However, some regions of mitotic chromosomes remain sensitive to nuclease activity (depicted here by a white triangle), indicating that some genes remain in open chromatin conformation, thus giving rise to the concept of gene bookmarking. Advances in cell biological (e.g., in situ immunofluorescence) and biochemical (e.g., chromatin immunoprecipitation) assays have allowed a direct examination of protein complexes (shown here by green and gray ovals and a red star) that are retained on target gene promoters during mitosis. In addition, certain histone modifications and variants that are associated with open chromatin conformation also have been observed on mitotic chromosomes. These observations together indicate that certain genes are bookmarked for expression immediately after mitosis, a mechanism that may be pivotal to the maintenance of cellular memory for growth and proliferation potential as well as for lineage identity in progeny cells.