Chromatin remodelling in mammalian differentiation: lessons from ATP-dependent remodellers

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Abstract
ATP-dependent chromatin-remodelling enzymes use the energy of ATP hydrolysis to alter histone–DNA contacts and to facilitate changes in chromatin structure. These are important steps in the regulation of gene expression, recombination and cell-cycle progression during cell differentiation. ATP-dependent chromatin-remodelling enzymes contribute to, and in many cases are essential for, organismal development and the initiation and/or completion of mammalian differentiation processes. The complexity of ATP-dependent chromatin-remodelling enzyme function might be increased by the presence of tissue-specific subunits and the ability to form different complexes from a pool of different subunit proteins. ATP-dependent chromatin-remodelling can be regulated by signal transduction pathways, thereby permitting extracellular cues to exert effects on chromatin structure. Regulation of changes in chromatin structure at specific loci frequently occurs in cooperation with chromatin modifying enzymes that post-translationally modify histone proteins. ATP-dependent chromatin-remodelling enzymes can have local effects on chromatin structure at specific loci, and can also have long-range effects that mediate changes over several kilobases or more. The targeting of ATP-dependent chromatin-remodelling enzymes to their sites of action occurs via DNA-binding regulatory factors that promote specific differentiation pathways. Targeting by related factors during differentiation might help to explain differences in the extent and timing of changes in chromatin structure and subsequent changes in gene expression. During the regulation of differentiation-specific gene expression, the consequences of ATP-dependent remodelling can result in gene activation or gene silencing. Moreover, the requirement for specific enzymes seems to be locus specific, despite the fact that multiple genes are responding to the differentiation cues with similar kinetics.