Polycomb Repressive Complex 2 Regulates Normal Hematopoietic Stem Cell Function in a Developmental-Stage-Specific Manner

Abstract

Summary Recent studies point to a pivotal role of polycomb repressive complex 2 (PRC2) in stem cell function and cancer. Loss of function approaches targeting individual PRC2 subunits have however generated findings that are difficult to reconcile. Here, we prevent assembly of both Ezh1- and Ezh2-containing PRC2 complexes by conditional deletion of Eed, a core subunit, and assess hematopoiesis. We find that deletion of Eed exhausts adult bone marrow HSCs, although fetal liver HSCs are produced in normal numbers. Eed null neonatal HSCs express HSC signature genes, but are defective in maintenance and differentiation. Comparative gene expression profiling revealed that neonatal and adult HSCs lacking Eed upregulated gene sets of conflicting pathways. Deletion of Cdkn2a, a PRC2 target gene, in Eed null mice enhances HSPC survival but fails to restore HSC functions. Taken together, our findings define developmental stage-specific requirements for canonical PRC2 complexes in normal HSC function.

Propagation of trimethylated H3K27 regulated by polycomb protein EED is required for embryogenesis, hematopoietic maintenance, and tumor suppression

“…Thus, Eed KI/+ BM HSCs were shown to have a cell-autonomous growth advantage. Our results are similar to those of previous studies reporting that the heterozygous null mutation of Eed confer a growth advantage for BM HSCs (7,12), whereas homozygous deletion of Eed in the hematopoietic cells results in severe HSC exhaustion only in the BM after birth (12). Therefore, complete loss of function and impaired function of EED appear to have different (possibly opposing) effects on BM hematopoiesis.…”

“…S3E). These results suggest that the reduced number of Eed KI/KI fetal liver cells is attributed mostly to a cell-extrinsic mechanism, which is supported by a previous study indicating that homozygous deletion of Eed in the hematopoietic organs caused no critical defects in the fetal liver earlier in midgestation (12). Thus, although the cause of embryonic death in Eed KI/KI mutants was unclear, our results demonstrate that the aromatic cage integrity of EED is required for proper embryonic development.…”

A Role for Monomethylation of Histone H3-K27 in Gene Activity inDrosophila

“…The enzyme responsible for K27 tri-methylation, PRC2, is present in single-celled eukaryotes and fungal species and it is highly conserved in plants and animals (SAWARKAR and PARO 2010), where it is centrally integrated into stem cell transcriptional programs (PEREIRA et al 2010;SURFACE et al 2010;XIE et al 2014). Although H3-K27me3 is fundamentally associated with developmental gene silencing, its mechanistic consequences are incompletely understood.…”

Functional Crosstalk Between Lysine Methyltransferases on Histone Substrates: The Case of G9A/GLP and Polycomb Repressive Complex 2

“…Eed mutant hematopoietic stem cells (HSCs) fail to differentiate into mature blood cells, showing that PRC2 coordinates diverse pathways to ensure proper selfrenewal and differentiation of HSCs in a developmental stage-specific manner (170). Interestingly, G9a/GLP have been also recently shown to regulate hematopoiesis (27).…”