Global modulation of chromatin dynamics mediated by dephosphorylation of linker histone H1 is necessary for erythroid...

Differentiation of metazoan cells involves dramatic changes in gene expression patterns and proliferative capacity driven primarily by epigenetic mechanisms. Here we used in vivo photobleaching techniques and biochemical assays to investigate the contribution of alterations in chromatin dynamics to the differentiation of murine erythroleukemia (MEL) cells, a model system for erythroid development. As MEL cells differentiate the binding affinity of all linker histone variants increases, indicative of an overall decrease in chromatin flexibility. Changes in H1(0) binding properties depend on phosphorylation at one or more of three cyclin-dependent kinase sites. The presence of constructs mimicking constitutively phosphorylated H1 results in a significant inhibition in the acquisition of commitment to terminal cell division and the expression of erythroid-specific properties. These data indicate that the progressive loss of cdk activity associated with MEL cell differentiation leads to the accumulation of dephosphorylated linker histones and restricted chromatin flexibility and that these are necessary events in the progression of erythroid differentiation. We present additional data indicating that the presence of phosphorylated H1 has a dominant effect on the binding behavior of other linker histones and propose a model for the role of linker histone phosphorylation in which these modifications act within the context of assembled chromatin.