Haematopoietic cell-fate decisions, chromatin regulation and ikaros

Heritable chromatin modifications have been described for both DNA and histones. Although our knowledge of DNA modifications is limited to methylation of CpG islands, a range of histone modifications is being revealed as 'codes' that determine chromatin activity. Histone codes can have direct effects on chromatin accessibility and they also provide additional layers of regulation through their interactions with other chromatin regulating factors. This provides an ingenious way to convey genetic information in a lineage-specific manner — information that is required not only to initiate but also to maintain the differentiated state. The activity of ATP-dependent remodellers is crucial in this series of chromatin regulatory events. Remodellers are powerful ATP-driven enzymatic machines that can alter chromatin structure irrespective of its configuration and thereby provide transient access to chromatin modifiers. This might trigger a series of chromatin regulatory events that underlie changes in gene expression required for lineage decisions. Ikaros is a lineage-regulating factor in the haematopoietic system. Lack of Ikaros impairs the production of lymphocyte progenitors/precursors and increases the production of their myeloid counterparts. In addition to an early role in lympho-myeloid cell-fate decisions, Ikaros seems to influence the outcome at a range of branch points of the lymphoid and myeloid pathways. An important mechanism of Ikaros action involves chromatin remodelling. In fact, Ikaros is an integral component of a 2-MDa complex containing both chromatin remodelling and modifying activities. The Ikaros–NURD (nucleosome remodelling and histone deacetylation) complex and its associated activities can trigger a series of chromatin regulatory events by providing accessibility to lineage-determining factors and their chromatin-modifying associates. In this way, Ikaros might support one of two alternative fates in differentiation by potentiating the required events in gene expression. The ability of Ikaros to target genes and nuclear compartments in a sequence-specific manner argues the case for gene-specific and global effects on chromatin regulation.