The role of chromatin modifiers in normal and malignant hematopoiesis

Abstract

Complex developmental processes such as hematopoiesis require a series of precise and coordinated changes in cellular identity to ensure blood homeostasis. Epigenetic mechanisms help drive changes in gene expression that accompany the transition from hematopoietic stem cells to terminally differentiated blood cells. Genome-wide profiling technologies now provide valuable glimpses of epigenetic changes that occur during normal hematopoiesis, and genetic mouse models developed to investigate the in vivo functions of chromatin-modifying enzymes clearly demonstrate significant roles for these enzymes during embryonic and adult hematopoiesis. Here, we will review the basic science aspects of chromatin modifications and the enzymes that add, remove, and interpret these epigenetic marks. This overview will provide a framework for understanding the roles that these molecules play during normal hematopoiesis. Moreover, many chromatin-modifying enzymes are involved in hematologic malignancies, underscoring the importance of establishing and maintaining appropriate chromatin modification patterns to normal hematology.

Figure 1

Histone modifications mark dynamically regulated genes. In all panels, shades of green indicate active marks, whereas shades of pink represent repressive marks. The orange and yellow colors mark regions of 5 mC and 5 hmC, respectively. (A) The distribution of histone methylation and acetylation marks, along with the degree of methylation, is illustrated across the promoter region, TSS (transcriptional start site), and gene body of a transcriptionally active gene. (B) Histone H3 methylation and DNA methylation are found in the promoter region and surrounding the TSS in transcriptionally repressed genes. (C) Bivalent chromatin domains consist of discrete pockets of histone H3K4me3 within large regions of histone H3K27me3. DNA 5hmC is also found in bivalent domains.

Figure 2

Modification-binding domains interpret histone PTMs. Domains from various histone-interacting proteins are depicted along with the PTMs that they bind on histone H3. Multiple reading domains can interact with a single modified site, as illustrated for histones H3K4, K9, K27, and K36. Interactions may also change depending on the modification present at the site, as shown for acetylation or methylation of histones H3K9 and K36. The colors represent different PTMs and associated binding domains, which are depicted as follows: pink, methylation; green, acetylation.