Non-canonical PRC1.1 Targets Active Genes Independent of H3K27me3 and Is Essential for Leukemogenesis

Abstract

Polycomb proteins are classical regulators of stem cell self-renewal and cell lineage commitment and are frequently deregulated in cancer. Here, we find that the non-canonical PRC1.1 complex, as identified by mass-spectrometry-based proteomics, is critically important for human leukemic stem cells. Downmodulation of PRC1.1 complex members, like the DNA-binding subunit KDM2B, strongly reduces cell proliferation in vitro and delays or even abrogates leukemogenesis in vivo in humanized xenograft models. PRC1.1 components are significantly overexpressed in primary AML CD34(+) cells. Besides a set of genes that is targeted by PRC1 and PRC2, ChIP-seq studies show that PRC1.1 also binds a distinct set of genes that are devoid of H3K27me3, suggesting a gene-regulatory role independent of PRC2. This set encompasses genes involved in metabolism, which have transcriptionally active chromatin profiles. These data indicate that PRC1.1 controls specific genes involved in unique cell biological processes required for leukemic cell viability.

H2A monoubiquitination in Arabidopsis thaliana is generally independent of LHP1 and PRC2 activity

“…1c, d; Additional file 2: Dataset S1; Additional file 1: Figure S4). These three differently marked subsets of genes have also been recently reported in animals [21, 38]. To identify possible differences between the two subsets of H2AK121ub-marked genes, we compared H2AK121ub coverage at H2AK121ub/H3K27me3- and only-H2AK121ub-marked genes (Additional file 1: Figure S5).…”

“…2a, e). A recent report in humans presented a PRC1 variant that binds and H2A monoubiquitinates genes involved in metabolism that are devoid of H3K27me3 and have a transcriptionally active chromatin profile [38]. A repressive role of H2A monoubiquitination at these genes is possibly overridden by the presence of other chromatin modifications involved in transcription activation or PRC1 might have a role in transcriptional activation, as has been previously proposed [39].…”

Epigenetics and Cancer Stem Cells: Unleashing, Hijacking, and Restricting Cellular Plasticity

“…Regardless of the specific mechanism, the commonality in all these cases is that cells become dependent on EZH2 to preserve their self-renewal potential, as a consequence of the cellular changes induced by transformation and other alterations occurring during tumor growth. Other PcG proteins such as a non-canonical PRC1.1 complex in AML [51] and BMI1 in glioma [52] exert similar functions. Histone modifiers in general have often been reported as positive regulators of CSC self-renewal (Table 1) 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64.…”

KDM2B is a histone H3K79 demethylase and induces transcriptional repressionviasirtuin‐1‐mediated chromatin silencing

“…5E). To characterize chromatin profiles near transcription start sites of H3K79me3-occupied genes that are sensitive to KDM2B depletion, we compared H3K79me3 peaks with published ChIP-seq studies for KDM2B in human acute myeloid leukemia cells (53). We noticed that alterations of H3K79me were correlated with KDM2B binding.…”