Abstract
Polycomb Group (PcG) proteins are epigenetic repressors of gene expression. The Drosophila Additional sex combs (Asx) gene and its mammalian homologs exhibit PcG function in genetic assays; however, the mechanism by which Asx family proteins mediate gene repression is not well understood. ASXL2, one of three mammalian homologs for Asx, is highly expressed in the mammalian heart and is required for the maintenance of cardiac function. We have previously shown that Asxl2 deficiency results in a reduction in the bulk level of histone H3 lysine 27 trimethylation (H3K27me3), a repressive mark generated by the Polycomb Repressive Complex 2 (PRC2). Here we identify several ASXL2 target genes in the heart and investigate the mechanism by which ASXL2 facilitates their repression. We show that the Asxl2-deficient heart is defective in converting H3K27me2 to H3K27me3 and in removing ubiquitin from mono-ubiquitinated histone H2A. ASXL2 and PRC2 interact in the adult heart and co-localize to target promoters. ASXL2 is required for the binding of PRC2 and for the enrichment of H3K27me3 at target promoters. These results add a new perspective to our understanding of the mechanisms that regulate PcG activity and gene repression.
Highlights
During the development and life of multicellular organisms, there is a need to set up and maintain distinct identities in different types of cells and tissues
To determine whether Secreted frizzled-related protein 2 (Sfrp2), Acta1 and G protein-coupled receptor kinase 5 (Grk5) are directly repressed by ASXL2 and Polycomb Repressive Complex 2 (PRC2), we examined enrichment of ASXL2 and PRC2 components at these loci by Chromatin immunoprecipitation (ChIP)-qPCR assays, focusing on regions between -2 kb and +2 kb of the transcription start sites (TSSs)
We have previously observed that the level of bulk H3K27me3 was reduced in Asxl2-/- hearts, suggesting an important role for ASXL2 in the homeostasis of the H3K27me3 mark [19]
Summary
During the development and life of multicellular organisms, there is a need to set up and maintain distinct identities in different types of cells and tissues. Epigenetic mechanisms play critical roles in the establishment and maintenance of cellular identity. The balanced action of PcG proteins and their antagonists, the Trithorax Group (TrxG) epigenetic activators, is crucial for the maintenance of Hox expression domains along the anterior–posterior axis [1,2]. It has since been discovered that PcG and TrxG proteins play essential roles in mammalian development, regulating the differentiation of a wide array of cell lineages [3,4,5]. The core components of PRC2, EZH2, SUZ12 and EED, are necessary and sufficient for PRC2’s histone methyltransferase (HMTase) activity [7,8,9,10]. The SET-domain protein EZH2 is the catalytic subunit [6,7]
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