Juxtaposed Polycomb complexes co-regulate vertebral identity

Abstract

Best known as epigenetic repressors of developmental Hox gene transcription, Polycomb complexes alter chromatin structure by means of post-translational modification of histone tails. Depending on the cellular context, Polycomb complexes of diverse composition and function exhibit cooperative interaction or hierarchical interdependency at target loci. The present study interrogated the genetic, biochemical and molecular interaction of BMI1 and EED, pivotal constituents of heterologous Polycomb complexes, in the regulation of vertebral identity during mouse development. Despite a significant overlap in dosage-sensitive homeotic phenotypes and co-repression of a similar set of Hox genes, genetic analysis implicated eed and Bmi1 in parallel pathways, which converge at the level of Hox gene regulation. Whereas EED and BMI1 formed separate biochemical entities with EzH2 and Ring1B, respectively, in mid-gestation embryos, YY1 engaged in both Polycomb complexes. Strikingly, methylated lysine 27 of histone H3 (H3-K27), a mediator of Polycomb complex recruitment to target genes, stably associated with the EED complex during the maintenance phase of Hox gene repression. Juxtaposed EED and BMI1 complexes, along with YY1 and methylated H3-K27, were detected in upstream regulatory regions of Hoxc8 and Hoxa5. The combined data suggest a model wherein epigenetic and genetic elements cooperatively recruit and retain juxtaposed Polycomb complexes in mammalian Hox gene clusters toward coregulation of vertebral identity.

Selection of Sensitive Methylation Markers for the Detection of Non-small Cell Lung Cancer

“…Since inactivation of tumor suppressor genes by aberrant promoter methylation play a potential role during tumorigenesis [37], it is possible that these genes function as tumor suppressors. For example, polycomb complexes were proposed to contribute to silencing of homeobox genes, and then initiates tumorigenesis [11,38]. The carcinogenic roles of these genes could be related to their mechanistic importance in embryo development.…”

“…Median methylation levels (sPMRs) in TFSLTs and lung tumor tissues were respectively 0. 38 Figure 1A. Methylation levels were significantly higher in NSCLCs than in TFSLTs for each of the five genes (P<2.2e-16 for each gene, Figure 1B).…”

Homeobox gene methylation in lung cancer studied by genome-wide analysis with a microarray-based methylated CpG island recovery assay

“…Polycomb complexes are involved in silencing of homeobox genes (36)(37)(38). A recent genome-wide analysis of the localization of Polycomb components including SUZ12, which is required for the histone methyltransferase activity and silencing function of the EED-EZH2 complex, has identified a large fraction of the targets as homeobox genes (39)(40)(41).…”

The regulation of Hox gene expression during animal development

“…A few studies identified some regions within vertebrate Hox clusters that could be involved in 'seeding' PcG activity (Kim et al, 2006;Woo et al, 2010). Of these, the best characterised is a phylogenetically conserved region between HOXD11 and HOXD12 that seems to be involved in homing PRC2 to the HOXD cluster in human stem cells (Woo et al, 2010).…”