Polycomb complexes in normal and malignant hematopoiesis

Abstract

Epigenetic mechanisms are crucial for sustaining cell type-specific transcription programs. Among the distinct factors, Polycomb group (PcG) proteins are major negative regulators of gene expression in mammals. These proteins play key roles in regulating the proliferation, self-renewal, and differentiation of stem cells. During hematopoietic differentiation, many PcG proteins are fundamental for proper lineage commitment, as highlighted by the fact that a lack of distinct PcG proteins results in embryonic lethality accompanied by differentiation biases. Correspondingly, proteins of these complexes are frequently dysregulated in hematological diseases. In this review, we present an overview of the role of PcG proteins in normal and malignant hematopoiesis, focusing on the compositional complexity of PcG complexes, and we briefly discuss the ongoing clinical trials for drugs targeting these factors.

Figure 1.

Mammalian PRC1/2 compositional complexity. (A) PcG proteins RING1A/B and PCGF1−6 compose a core around which accessory subunits associate. cPRC1 incorporates one PHC and one CBX protein. Noncanonical PRC1 (ncPRC1) complexes incorporate RYBP/YAF2 along with specific sets of additional proteins. (B) PRC2 shares a similar organization, with a tetrameric core composed of EZH1/2, SUZ12, EED, and RBBP4/7. Association with PCL proteins defines a PRC2.1 subtype that can associate with either EPOP or PALI1/2 (PRC2.1a/b). Conversely, association with AEBP2 and JARID2 defines a PRC2.2 subtype.

Figure 2.

PRC1/2 in normal adult hematopoiesis. Schematic representation of the hematopoietic differentiation according to the classical model. PRC complexes that were described to have a role in regulating gene expression at specific stages are shown along with their reported genomic targets. Adapted from Corces et al. (2016).