Ezh2 controls B cell development through histone H3 methylation and Igh rearrangement

Abstract

Polycomb group protein Ezh2 is an essential epigenetic regulator of embryonic development in mice, but its role in the adult organism is unknown. High expression of Ezh2 in developing murine lymphocytes suggests Ezh2 involvement in lymphopoiesis. Using Cre-mediated conditional mutagenesis, we demonstrated a critical role for Ezh2 in early B cell development and rearrangement of the immunoglobulin heavy chain gene (Igh). We also revealed Ezh2 as a key regulator of histone H3 methylation in early B cell progenitors. Our data suggest Ezh2-dependent histone H3 methylation as a novel regulatory mechanism controlling Igh rearrangement during early murine B cell development.

Linking the epigenetic ‘language’ of covalent histone modifications to cancer

“…Mice deficient for EZH2 showed impaired early B-cell development and decreased rearrangement of the immunoglobulin heavy chain (IgH). Since EZH2 has been shown in this study to specifically methylate lysine 27 in H3, it is plausible that EZH2 absence reduces both basal and interleukin-7-induced histone H3 lysine methylation, although the exact mechanism(s) remains elusive (Su et al, 2003). Since EZH2 plays a role in B-cell development in mice, it will be interesting to see, if human lymphomas show an increased methylation of lysine 27 (and possible lysine 9) in histone H3 at EZH2 target genes.…”

“…The Drosophila E(Z) protein is shown to methylate lysines 9 and 27 in H3, and causes stable changes in the chromatin, leading to the repression of target genes (Su et al, 2003). Overexpression of the human E(Z) homologue EZH2 has been observed in prostate cancer and lymphomas, and is linked to increased cell proliferation (Sellers and Loda, 2002;Varambally et al, 2002).…”

Epigenetic regulation of aging stem cells

“…Another PcG gene implicated in adult stem cell function during aging is enhancer of zeste 2 (Ezh2), which comprises the methyltransferase activity of PRC2 (Kuzmichev et al, 2002;Muller et al, 2002;Ketel et al, 2005). In the hematopoietic system, Ezh2 does not appear to be required for stem and early progenitor cell function under normal steady-state conditions, as deletion of Ezh2 in all adult hematopoietic lineages causes a block in B-cell lineage production, but not in other lineages (Su et al, 2003). However, lentiviral-mediated overexpression of Ezh2 in transplanted bone marrow of young mice enhances long-term repopulating capacity of HSCs upon serial transplantation (Kamminga et al, 2006).…”

Triptolide Inhibits Histone Methyltransferase EZH2 and Modulates the Expression of Its Target Genes in Prostate Cancer Cells

“…EZH2 performs its epigenetic role via regulation of histone methylation, and functions as the sole catalytic core subunit of the polycomb repressive complex 2 (PRC2), which catalyses the trimethylation of histone3 on lysine 27 (H3K27me3) and is implicated in gene repression. EZH2 serves in many fundamental biological processes, including embryonic development (O'Carroll et al, 2001), X chromosome inactivation (Plath et al, 2003), B cell development (Su et al, 2003) (Su et al, 2005), maintenance of circadian clock function (Etchegaray et al, 2006), cell differentiation (Gil et al, 2005), senescence (Kamminga et al, 2006) and transcriptional activation (Shi et al, 2007). Increasing evidences imply that deregulation of EZH2 closely correlates with tumors.…”