Polycomb and trithorax opposition in development and disease

Polycomb and trithorax group proteins control Hox gene expression. Appropriate spatial and temporal expression of Antennapedia Complex (ANT‐C) and Bithorax Complex (BX‐C) genes in Drosophila melanogaster is required for proper anatomical patterning in developing embryos. Intriguingly, the expression pattern of each of these clusters along the embryonic anterior‐posterior axis mirrors their collinear arrangement along their respective chromosomal location. The BX‐C, comprised of Ubx, abdA, and AbdB, controls the development of the posterior two‐thirds of the embryo. Selected mutations mapped to these loci (shown above the each gene in red) cause homeotic transformations toward more anterior segments. The ANT‐C, comprised of lab, pb, Dfd, Scr, and Antp, controls the development of the anterior segments of the fly embryo including the head and prothorax (non‐homeotic genes including zen, ftz, and z2 have been omitted from this figure). Mutant alleles in this locus (also shown above the respective genes in red) cause a variety of homeotic transformations in the anterior portion of the fly. A subclass of these mutations, including the Ns mutation, result in the eponymous antennapedia transformation in which antennae develop as leg structures.

Two sub‐families of BAF chromatin remodelers: BAF and PBAF. Both BAF and PBAF complexes have ATP‐dependent chromatin remodeling ability, and both complexes can recruit ancillary protein factors and transcriptional machinery. Although the general chromatin remodeling functionality of these complexes is understood, genomic targeting specificities during development and disease are still uncertain. Furthermore, how these complexes are formed, and how the core subunits are apportioned to maintain a balance between BAF and PBAF remains to be determined.

Transcriptional repression by polycomb repressor complex 1 (PRC1) and polycomb repressor complex 2 (PRC2) Is Multi‐Faceted. (a) PRC1 mono‐ubiquitinates histone 2A at lysine 119 (H2AK119Ub1) at genes targeted for transcriptional repression. In the absence of histone methyl marks (i.e., H3K27me3) PRC1 can bind to DNA via RYBP, YAF2, and other ancillary factors in order to propagate repressive H2AK119Ub1. Deposition of H2AK119Ub1 can be reversed by deubuiquitinase (DUB) proteins including 2A‐DUB, Ubp‐M, USP21, and USP7. (b) The catalytic subunit of PRC2, EZH2, is capable of mono‐, di‐, and tri‐ methylating H3K27, with the trimethyl mark being the stable mark of heterochromatin formation and subsequent transcriptional repression. Both UTX and JMJD3 demethylases are capable of antagonizing H3K27me3 mediated repression by reducing H3K27me3 to H3K27me1 through sequential demethylation. (c) The canonical PRC1 can bind to H3K27me3 through its CBX chromodomain allowing for H2AK119Ub1 deposition and further reinforcing a repressive environment. (d) Alternatively, non‐cannonical PRC1 has recently been suggested to function as a frontier complex by binding to DNA through KDM2B allowing for primary H2AK119Ub1. This is followed by PRC2 mediated H3K27me3 via interactions with ubiquitin that are mediated by JARID2 and AEBP2.

Throughout evolution the BAF complex diverged into two distinct complexes: the BAF complex (BAP complex in Drosophila) and PBAF complex (PBAP complex in Drosophila). Furthermore, in mammals several subunits obtained multiple paralogues including BAF45A/B/C/D, BAF60A/B/C, BAF155/170, BAF250A/B, BAF53A/B, Brd7/9, and the catalytic subunits Brg/Brm. The COMPASS complex also developed greater structural and functional diversity during evolution. While the Set1/COMPASS complex was maintained in both Drosophila and mammals, additional COMPASS‐like complexes have been identified including the trx/COMPASS‐like complex (MLL1/2/COMPASSlike in mammals), and the trr/COMPASS‐like complex (MLL3/4/COMPASS‐like in mammals).

The evolution of Polycomb PRC1 and PRC2 complexes occurred similarly with both groups obtaining greater structural and functional diversity in mammals. Polycomb repressor complex 2 (PRC2) is the least altered over evolutionary time with the catalytic subunit E(z) and the ancillary subunit Pcl being the only subunits to expand into multiple paralogues, EZH1/2 and PCL1/2/3, respectively. Greater complexity is exhibited in the mammalian polycomb repressor complex 1 (PRC1) compared to its Drosophila counterpart. While all mPRC1 variants appear to have a stable core of RING1A/B and one of the six PCGF paralogues, two general sub‐groups exist as defined by the presence of other protein subunits. The first is the canonical sub‐group that is characterized by one of three PHC paralogues and one of five CBX paralogues. The second is the non‐cannonical subgroup that is characterized by the absence of PHC and CBX type proteins and the presence of either RYBP or YAF2. Dashed outline indicates an ancillary subunit. *Indicates that both PCGF and CBX have several paralogues within these complexes.

Mutations of BAF subunits are thought to drive oncogenesis through both loss‐of‐function and gain‐of‐function mechanisms. In this figure, a BAF subunit (in green) is lost due to deletion (or nonsense) mutations resulting in haploinsufficiency or loss of heterozygosity, or carries truncation or missense mutations that affects a functional region (highlighted in yellow). Loss of this BAF subunit could possibly result in paralogue compensation (replaced by red BAF paralogue) leading to gain and/or loss of function at crucial regulatory genes (left and right pictures, respectively). Similarly, BAF subunit loss could also result in destabilization of BAF complexes with gain and/or loss of function outcomes due to residual aberrant complexes (top right and bottom left pictures, respectively). Truncation or missense mutations that affect a functional region could also lead to gain of function due to mistargeting to oncogenes (top left picture) or loss of function (bottom right picture) due to inability to target crucial tumor suppressor genes for activation.