The phosphatase interactor NIPP1 regulates the occupancy of the histone methyltransferase EZH2 at Polycomb targets.
Polycomb group (PcG) proteins are key regulators of stem-cell and cancer biology. They mainly act as repressors of differentiation and tumor-suppressor genes. One key silencing step involves the trimethylation of histone H3 on Lys27 (H3K27) by EZH2, a core component of the Polycomb Repressive Complex 2 (PRC2). The mechanism underlying the initial recruitment of mammalian PRC2 complexes is not well understood. Here, we show that NIPP1, a regulator of protein Ser/Thr phosphatase-1 (PP1), forms a complex with PP1 and PRC2 components on chromatin. The knockdown of NIPP1 or PP1 reduced the association of EZH2 with a subset of its target genes, whereas the overexpression of NIPP1 resulted in a retargeting of EZH2 from fully repressed to partially active PcG targets. However, the expression of a PP1-binding mutant of NIPP1 (NIPP1m) did not cause a redistribution of EZH2. Moreover, mapping of the chromatin binding sites with the DamID technique revealed that NIPP1 was associated with multiple PcG target genes, including the Homeobox A cluster, whereas NIPP1m showed a deficient binding at these loci. We propose that NIPP1 associates with a subset of PcG targets in a PP1-dependent manner and thereby contributes to the recruitment of the PRC2 complex.
Van Dessel
Nele
N
Laboratory of Biosignaling and Therapeutics, Department of Molecular Cell Biology, Faculty of Medicine, KULeuven, B-3000 Leuven, Belgium.
Beke
Lijs
L
Görnemann
Janina
J
Minnebo
Nikki
N
Beullens
Monique
M
Tanuma
Nobuhiro
N
Shima
Hiroshi
H
Van Eynde
Aleyde
A
Bollen
Mathieu
M
D001665:Binding Sites; D002460:Cell Line; D002843:Chromatin / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis*; D004722:Endoribonucleases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis*; D006801:Humans; D010749:Phosphoprotein Phosphatases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000032:analysis*
D002843:Chromatin; D004268:DNA-Binding Proteins; D063146:Polycomb-Group Proteins; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; D000076983:Histone Methyltransferases; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2; D004722:Endoribonucleases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C097081:PPP1R8 protein, human