SUMO-Specific Protease 2 Is Essential for Suppression of Polycomb Group Protein-Mediated Gene Silencing during Embryonic Development

Abstract

SUMMARY SUMO-specific protease 2 (SENP2) has a broad de-SUMOylation activity in vitro. However, the biological function of SENP2 is largely unknown. Here, we show that deletion of SENP2 gene in mouse causes defects in the embryonic heart and reduces the expression of Gata4 and Gata6, which are essential for cardiac development. SENP2 regulates transcription of Gata4 and Gata6 mainly through alteration of occupancy of Pc2/CBX4, a Polycomb Repressive Complex 1 (PRC1) subunit, on its promoters. We demonstrate that Pc2/CBX4 is a target of SENP2 in vivo and that SUMOylation is essential for Pc2/CBX4-mediated PRC1 recruitment to methylated histone 3 at K27 (H3K27me3). In SENP2 null embryo, SUMOylated Pc2/CBX4 accumulates and Pc2/CBX4 occupancy on the promoters of PcG target genes is markedly increased, leading to repression of Gata4 and Gata6 transcription. Our results reveal a critical role for de-SUMOylation in the regulation of PcG target gene expression through a novel mechanism.

The Dynamics and Mechanism of SUMO Chain Deconjugation by SUMO-specific Proteases

“…Genetic knock-outs or cellular knock-downs of deSUMOylating enzymes can highlight the requirement for the protein itself, but unless the knock-down is accompanied by reconstitution with a catalytic mutant (18,47,49) one cannot determine whether the catalytic activity or just the presence of the protein is required. The application of cleavage-resistant mutants takes an orthogonal approach in defining the importance of substrate cleavage on a more global scale, which would be cumbersome to achieve by one-by-one knock-down of SENPs.…”

Pcgf5 Contributes to PRC1 (Polycomb Repressive Complex 1) in Developing Cardiac Cells

“…Among Cbx proteins, Cbx4 may play an important role in cardiogenesis. SUMO-specific protease 2 (SENP2) was reported to regulate transcription of Gata4 and Gata6, mainly through alteration of the occupancy of Cbx4 on their promoters [5]. In SENP2-deficient embryos, sumoylated Cbx4 accumulates on the promoters of target genes, leading to transcriptional repression of Gata4 and Gata6.…”

“…Traditionally, focus on causes of CHD has involved transcriptional networks during cardiogenesis, because correct alignment and septation of cardiac structures regulated by cardiac specific transcriptional factors, such as Tbx1, Tbx5, Tbx20, Gata4, and Nkx2-5, are essential for cardiac morphogenesis [1]. In addition to these multiple genetic factors, recent studies have shown that some chromatin remodeling factors moderate gene expression to control cardiogenesis and are also involved in the molecular pathogenesis of CHD [2][3][4][5][6][7].…”

Regulation of Protein-Protein Interactions by the SUMO and Ubiquitin Pathways

“…The regulatory function of SENPs is biologically relevant in development. SENP3/5 are required for ribosomal biogenesis, and targeting SENP2 during cardiac development impairs the expression of key cardiac factors Gata2 and Gata6 (Yun et al, 2008;Kang et al, 2010). Specifically, in SENP2 null embryos, SUMOylated polycomb group Pc2/CBX4 complex accumulates on the promoters of PcG target genes, leading to repression of Gata4 and Gata6 transcription.…”

“…SENPs also play a key role in tumorigenesis; expression of SENP1 transforms prostate cancer cells and activates Androgen Receptor (AR) signaling. In addition, SENP3 regulates angiogenesis via its impact on HIF1α-associated coactivator p300, and elevated mRNA levels of SENP6, 7 are linked to breast cancer (Cheng, 2010;BawaKhalfe & Yeh, 2010).…”