Transcription factor-mediated epigenetic regulation of cell growth and phenotype for biological control and cancer

Abstract

There is a requirement to retain regulatory information and parameters of nuclear organization during cell division when transcription is globally silenced to sustain competency for expression of genes that control proliferation, cell growth and phenotype in progeny cells. Histone modifications, DNA methylation and RNA-mediated silencing are well defined, DNA-independent epigenetic mechanisms that regulate gene expression. Recent results suggest that retention of lineage-specific transcription factors with promoter elements and sequential assembly of gene regulatory machinery is a novel parameter of epigenetic control to sustain cellular identity post-mitotically. Collectively, these epigenetic signatures “bookmark” genes for activation or suppression as cells exit mitosis and resume cell cycle progression. We propose a model for cell fate and lineage commitment, coordination and maintenance where the regulatory proteins are retained on mitotic chromosomes to convey information for biological control to progeny cells as well as for controlling expression of the transformed and tumor phenotypes. MicroRNAs are another dimension to transcription factor-mediated epigenetic regulation of gene expression in biological control and cancer. Our findings demonstrate that fidelity of transcription factor localization is required for microRNA-related activation and suppression of regulatory networks in myeloid progenitor cells providing a novel and selective epigenetic target for treatment of acute myelogenous leukemia.