Cell differentiation entails early lineage choices leading to the activation, and the subsequent maintenance, of the gene expression program characteristic of each cell type. Alternative lineage choices involve the activation of different regulatory and coding regions of the genome, a process instructed by lineage-determining transcription factors, and at least in part mediated by the deposition of chromatin marks that modify functionality and accessibility of the underlying genome. According to classic epigenetics, subsequent maintenance of chromatin marks across mitoses and in spite of environmental perturbations occurs largely through autonomous and unsupervised mechanisms. However, paradigmatic genetic and biochemical studies in immune system and hematopoietic cells strongly point to the concept that both induction and maintenance of the differentiated state require constant supervision by lineage-determining transcription factors, which may act to globally organize the genome in both the one- and the three-dimensional space.
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