Multicellular organisms depend on the precise orchestration of gene expression to direct embryonic development and to maintain tissue homeostasis through their life spans. Exactly how such cell type–specific patterns of gene expression are established, maintained, and passed on to the next generation is one of the most fundamental questions of biology. Eukaryotes package their DNA into nucleosomes to form chromatin fibers. Chromatin plays a central role in regulating accessibility to DNA in many different DNA templated processes, including machineries that transcribe DNA into RNA, i.e., transcription. Transcriptional control through sequence-specific DNA binding factors (transcription factors) is well established; however, proteins that change chromatin structure (chromatin modifiers and remodelers) provide an additional layer of regulation and are considered major epigenetic determinants of cell identity and function. Among the numerous chromatin modifiers, the members of the Polycomb group (PcG) and the Trithorax group (TrxG) of proteins, in particular, have been scrutinized genetically and biochemically for decades. However, new and unexpected functions for these complexes are constantly emerging because of the intense interest in the critical role these proteins play in maintaining a balanced state of gene expression.

In the classical view, PcG and TrxG proteins regulate the repressed and activated states of gene expression, respectively. Both PcG and TrxG are organized in multiprotein complexes, which include the Polycomb repressive complex 1 and 2 (PRC1 and PRC2, respectively), and the complex of proteins associated with Set1 (COMPASS) family. Polycomb and COMPASS families are well known for their opposing roles in balancing gene expression, a phenomenon initially characterized using classical Drosophila melanogaster genetic approaches at a time when their biochemical functions were still unknown. Later studies demonstrated that Polycomb and COMPASS complexes have enzymatic activities modifying different sites on a common target, the nucleosome. Nucleosomes can be posttranslationally modified in a variety of ways, many of which strongly correlate with different states of gene expression. Through their ability to regulate gene expression, several components of both the Polycomb and COMPASS complexes are involved in a plethora of crucial biological processes ranging from the regulation of embryonic development to widespread involvement in neoplastic pathogenesis.

Recent genome-wide studies have demonstrated that a large number of the components of the Polycomb and COMPASS families are often mutated in different forms of cancer. Some mutations result in gene deletion or early termination, such as loss-of-function (LOF) mutations, whereas gain-of-function (GOF) mutations increase or change their normal activities. Although it cannot be excluded that some of those are passenger rather than driver mutations, they suggest a relevant function of these proteins in tumorigenesis. Moreover, animal models have provided convincing evidence supporting a role for these complexes in tumor progression. However, even after decades of study, how Polycomb and COMPASS control normal or aberrant gene regulatory networks is not fully understood yet. From the perspective of their catalytic activities, the degree to which catalytic versus noncatalytic functions contribute to their roles in development and cancer has just begun to emerge. Concurrently, the possibility that PcG and TrxG enzymatic activities modify non-nucleosome substrates remains a fascinating�…